The way Lero is initially treated by many ponies when he initially arrives in Equestria. Despite trying extremely hard to fit in and become a productive member of the community, he still ends up being shunned by most of the town due to their fear of him. Thankfully it gets better.
Rainbow Dash's self-esteem problems after having bad luck romantically. Being extremely strong, slender, and having a lack of 'bounce', she has an extremely hard time attracting any stallion's interest. The few she did manage to either admitted they were doing it for a dare, or quickly blew her off for more attractive mares.
To top it off, when she finally finds someone, she still gets insulted and mocked over it.
While Honeybee is not a particularly nice pony in her own right, her sister Honeydew shows a complete lack of concern for the fact that her sister almost drowned, all because of her vendetta against Lero.