What do you do when the odds are stacked against you?

I know for a fact that it IS possible to WORK very hard and be very SMART, but still not come out successful. I'd say that because sometimes life has its strikes against you like family issues and personal health problems, no matter how much hard work you put in and surround yourself with the right people you still won't succeed because the odds are stacked against you. 

The question is, how does one get out of a situation like this? Do you dump the family, friends and move elsewhere? What is the right strategy? Just say I quit?

Any comments, support would be welcome.