Madagascar and Peru, the only two areas in the game with only one way to infect them.
Western Europe was the original Pandemic's Madagascar. It had no airports or water sources. If you didn't hit it quickly, it would become the last bastion of civilization. Even worse, starting in Central Europe doesn't even assure you'll get it.
Even Better Sequel: Although it's by no means bad, the original game pales in comparison to the second.
Game-Breaker: Mimicking the flu symptoms minus everything dangerous means that your disease will spread everywhere, including to Madagascar early on, giving you plenty of points to spend on fun things like heart failure. Giving your disease moisture I and heat I also helps a lot with infecting Madagascar.
Harsher in Hindsight: Every once in a while, countries will be hit by natural disasters and other issues, some of which have happened in Real Life (such as "New Zealand gets hit by earthquake").
The game as a whole could be considered Harsher now that there is an Ebola outbreak spreading around Africa and potentially to other countries throughout the world.
Hilarious in Hindsight: Madagascar really did SHUT DOWN EVERYTHING after the "zombie incident" in Florida where a man got high on bath salts and tried to eat a homeless man's face.
Memetic Badass: Thanks to this game, Madagascar will always be remembered as the sole area in the world that no epidemic can touch.
Broken Base: Which edition has the better artwork? Some prefer the more realistic and painterly style of the first edition, while others like the higher budget TV show-esque artwork of the second. The fact that On The Brink was the only expansion to be done in the style of the first, and all future expansions are done exclusively in the second has broken the base further.
HSQ: Legacy's first twist is that one of the diseases is incurable, and the game only gets crazier from there.
Most Wonderful Sound: Winning the iOS adaptation transforms the classic map into a globe's normal blue-green colors, with soft, victorious music playing.
Scrappy Mechanic: The roles are supposed to be randomly allocated, but this is a controversial rule given that some roles are more valued than others. This isn't so bad in the base game where there are only 7 roles and you are going get at least one or two you can build a strategy around, but as the expansions increase the number of roles to 20+, players are more likely to end up with a team that struggles to synergise well. The most common kind of House Rules are those that allow the players to select their roles directly, or at least give them a greater degree of control over what role they are assigned. Cthulhu has the mechanic of players choosing one of two roles handed to them, and handing the unselected role and a new role to choose from to the next player.