Just from working on eNotes for years, and consequently working with editors from both American and Britain, I totally agree with pohnpei397. As an American, I always do a double take at the words "honour" and "colour" from our British editors. It is the same (maybe worse?) with words like "analyse" and "specialise." As mentioned above, it's all about the letters "u" and "s."
I thought it might be fun to explore another difference, not with spelling this time, but with punctuation. It seems to be tradition in Britain to put the period outside of the quotation marks instead of the MLA-inspired inside the quotation marks.
This particular issue of where the period belongs truly drives me nuts (in that it is one of my pet peeves). The interesting thing is, eNotes doesn't mind British spelling, but wants to remain consistent in regards to quotations! A good thing for persnickety me, I guess. : )
The main differences in spelling have to do with the letter "u" and the letters "c" and "s."
In British English, "u" is often used in words where it is not in American English. For example, there is "labour" as opposed to "labor" and "colour" as opposed to "color."
In British English, the soft "c" is often used where Americans would use "s" (or sometimes z). For example, there is "defence" as opposed to "defense" and "pressurise" as opposed to "pressurize."