Any Polaris ship in EV Nova. Ships built by the Federation, the AuroranEmpire, the Rebels, or the pirates are pretty evenly matched. One player reported he took down a Federation Carrier using a mass-moddednote take a freighter with a good-size cargo bay, then use mass expansions to turn most of the bay into more room for weapons Pirate Enterprise freighter rigged for More Dakka. But any Polaris ship eats its analogs from the other governments for lunch. In particular the Federation and Aurorans have no counter for the Polaris Raven other than mobbing it and hoping for the best.
In general, mouselook on the PC ports of the various installments. You could fire machine guns and assault rifles with pinpoint accuracy, fire out of cars at enemies much more easily and pick targets far off with sniper-like precision, regardless of what weapon you were using. Using helicopters in all the entries after Vice City also allowed the player to avoid many of the problems that were specifically set up to hinder drivers - once you know where to get one, you'll never need to use a car again outside of required missions.
The Hunter chopper. Vigilante missions are a lot easier when you have a death-spewing military attack helicopter to do them with. Play the mission for thirty minutes without resetting and you end up with more money than you can ever possibly spend.
If you know where to look, you can obtain high-tier guns with plenty of ammunition and tons of explosives for free, long before they're available for purchase. These pickups respawn when you save or after six in-game minutes. When you're doing an early to mid-game mission when enemies come at you with handguns or UZI's, you can fight them with an assault rifle, an automatic shotgun or rocket launcher you didn't pay a single cent for.
The M-16 in Grand Theft Auto III was easily the most overpowered weapon in the game. Available early on, the M-16 shredded everything that stood in its path - cars, people, law enforcement, you name it.
The Vice City equivalent was the Minigun.
In Vice City, collecting 30 hidden packages (which can be done right at the start of the game) gives a Colt Python spawn at Tommy's safehouse. It's a One-Hit Kill on most enemies, with the only drawback being a slower rate of fire.
Grand Theft Auto: San Andreas features a special gambling system linked to a luck stat, whereby you can only bet based on your gambling skill. It then tosses the whole thing out the window with Inside Track Betting, a horse racing gambling shop with no upper limit to bets. And one of them is right near a save point. So, bet the long shot, reload if it doesn't win, save if it does, and repeat this; you'll quickly have more money than you could ever possibly spend.
Grand Theft Auto: Vice City Stories: By taking over a few businesses, building High-Rollers and doing their missions early on, you can easily get 5-digit income every day... and you can speed through time by repeatedly getting Wasted or Busted. Combine this with the Minigun (although in all fairness, you can't get this until near the end of the game, but before that there are many other great weapons too), which thanks to your high income you can easily afford, and the game becomes a walk in the park.
The automatic shotgun in Grand Theft Auto IV: The Ballad of Gay Tony. All of the stopping power, no limited range and explosive shells means you can blow up a car or helicopter in just two hits. Far and away the best weapon in the game, and available early.
Beating the Hitman missions in Saints Row 2 will cause you to have unlimited rifle ammo. The Sniper Rifle can destroy a car in 2-5 bullets. Beating Corporate Warfare will give you unlimited RPG ammo, and can make those hard as hell car battles end in a few shots(did I forget to mention that getting the Annihilator will make things easier, and it still applies in a new game even if you didn't beat CW on the new save).
That is nothing. Saint's Row 2 will also give you, as a present for defeating certain minigame missions, an infinite ammo shotgun that can shred tanks and infinite ammo dual-wielded fully-automatic magnum pistols that can shred deities. This is just for beating minigame missions. Which are available the moment you step into the world. Meaning, in effect, the moment you leave the Starter Zone, you can beeline for these specific minigame missions and become a God of Death before embarking on the storyline missions.
But what about some of the trickier vehicle-based missions, you say? Well, apart from those dual-Cobras devouring anything in the universe, you can also pretty easily get your Wanted level up to the utmost and look around - not too hard, honestly, they will be everywhere - for one of those Spec Ops AP Cs(the 'Bear') with the mounted gatling guns on the top. Jack one (also easy, as most of them are being used for barricades instead of chasing you, for some reason) and get it to a safehouse. Voila! Problem permanently solved. Get it to a garage and soop it the fuck up and you're basically golden, what with having an armor-plated death engine with a mounted gatling cannon with default infinite rounds on the top. There is basically nothing in the universe that can stand against you. Haaaave fun!
Incendiary ammo for your submachine guns. Any enemy hit with even a single round is set on fire and takes continual damage, which means most ordinary grunts are going to die very rapidly. Non-Brute enemies are, furthermore, completely incapacitated, as they run around trying to put themselves out instead of shooting at you. And if a flaming enemy touches another enemy, that enemy also gets set on fire. This makes any gunfight in which your enemies stay grouped together (which is most of them) very easy.
Oleg Kirrlov, one of your "homies," is a Brute who fights on your side, with all the benefits you'd imagine would come of having a nigh-invulnerable juggernaut (who can be rapidly revived and restored to full health if something does bring him down) at your command. The only downsides are that he's very big and will turn on you if hit with friendly fire and that he can only ride around in one specific kind of vehicle, so travel can be a bit of a pain.
The SA-3 Airstrike, which you receive about halfway through the game. Pull it out, point it at a group of enemies, hold down the trigger for a few seconds, then step out of the blast radius. Makes gang operations and survival missions a breeze.
One of your vehicle delivery upgrades is a tank delivery. Yes, an actual tank. On demand.
And later, you get a VTOL on demand. The boss sums the vehicle up as being like "a helicopter that doesn't suck!"
At around Respect 50, you can buy character upgrades that make you basically immune to everything except melee damage and being in a car when it explodes. Although, if you're at Respect 50, there's probably not much left the game can throw at you anyway unless you went out of your way to farm respect before doing anything else.
One DLC allows you to purchase a jet. An incredibly powerful jet that you can use to navigate the city at high speeds. It's only deployable in a very small number of areas (anyplace you can deploy a chopper), but it allows you to reach any destination in record time. Just don't forget where you parked.
Early in Red Faction Guerrilla, Sam will invent the Arc Welder. Buy it, upgrade it, and never look back. This thing will not only fry the three nearest enemies (either killing them or setting them up for a hammer blow), it can somehow distinguish friend from foe, making it safe to use around valuable NPCs. Most important, it'll kill the driver of any vehicle, from the humblest car to the mightiest tank... leaving it undamaged for you to use. Many missions that would otherwise be tough are a snap with this glorified power tool.
Terraria has the various Dungeon Chest weapons, all of which are Purposely Overpowered due to the incredible rarity of finding a key for the chest.
The Vampire Knives throws a spread of knives that steal health from whatever they hit. They have been nerfed somewhat, but they're still considered one of the best melee weapons in the game.
The Piranha Gun fires a mechanical piranha that latches onto its target, dealing constant damage as long as the player holds down the mouse button.
Nord Huscarls. Pack them in a tight group of 20-30 and they'll inflict massive casualties on anyone who is foolish enough to try and take them head on. And don't think you're safe doing hit-n-run either; their thrown axes are pretty much One Hit Kills to anyone who isn't a plate-armoured knight.
Rhodok Sharpshooters. They're armed with a Siege Crossbow which deals sixty-something damage per shot (in a game where 50-100 HP is common), and they hit with pinpoint accuracy. They're armed with a huge pavise shield (the only archers in the whole game to get shields) that stops the projectiles of your own units and makes them fairly decent in hand-to-hand as well.
Vaegir Marksmen. Not as good in hand-to-hand and less powerful per shot as their Rhodok crossbowman cousins, but they shoot just as accurately and much much faster, and worse, they often turn up in larger groups. Taking castles from any faction is tough, but taking Vaegir castles is nightmarish.
The Surgery skill. 4% chance per point that a unit will be knocked unconscious rather than killed. Doesn't sound like much, but remember that soldiers who survive battles and get experience are much stronger. Stronger soldiers are much harder to kill and much better at killing other soldiers, so you win more battles with fewer casualties. You win more battles, and you get more experience for your elite killing machines and your raw recruits due to Leaked Experience, and they in turn become much harder to kill... See how there's a snowball effect here? You only need about 3-4 points in the skill for a noticeable effect, and it becomes even more broken if you take up the Trainer skill as well, which allows you to distribute a small amount of experience points from just randomly marching around.
Plate armour. So you move at the same speed as a pregnant whale when walking? So what when 5 out of 6 times you're hit, you won't take any damage!? And you're probably riding a horse too! There's a good reason why plate armour is far and away the most expensive equipment in the whole game. Second-tier armours are far cheaper, and still increase your survivability ten-fold.