One human interaction scenario that gives me pause is self-deprecation. This is something I do myself quite frequently ("I forgot to do that because I'm worthless"). I always mean it in a joking sense; I really don't think I suck all that much. But, I can't always tell if other people mean it or not. I just tend to assume that they are also joking, even though it's never true. So, I'm pretty terrible at appropriately responding to this situation.
Probably the socially correct thing to do in these situations is to be encouraging and uplifting to the person, especially if they deserve it. But it seems to me that anyone who knows me well enough would see right through that. I wouldn't be being sincere; I don't do encouraging and uplifting. So, I usually just emit an awkward laugh and continue on as if the person never said anything, because awkward and oblivious is something I do do.