I think there's a bunch of them that are important, so I'll list mine in order with a short opinion of why.
-Terrorism...because a few good hits against strong nations could disrupt the entire world for decades. Couple that with terror-sponsoring nations acquiring nuclear weapons, because the transfer could be made and pretty much destroy our economy and our way of life.
-Entitlements...the idea that someone else will take care of us promotes laziness and apathy, although it seems on the surface to be humane and good.
-Immigration...has an effect on health care, because nobody can be refused treatment for lack of payment (Hippocratic oath, I believe). Also affects ability of terrorists to enter the country. I don't care about the work thing so much, because a lot of the jobs they come over and take are low-paying jobs that nobody here wants anyway, but that doesn't stop us from complaining.
-Health care...what a mess. I don't think socialism works in this field because of my liberal friend in the UK who hates it (OK, only one first-hand source) along with philosophical differences, but I think that capitalism is a problem as well. I also don't want to pay for someone else's who will never pay it back (not selfishness, just efficiency and fairness...see above entitlements), so good luck with this one. I do have a few ideas, but not for here yet.
-Taxes...I'd love to see a consumption tax like the one out there called the Fair Tax, but I think it won't fly because it seems too good to be true and Americans love our tax refunds at the end of the year and writeoffs. Lump Social Security in here too, because it's a tax and needs fixing.
-Energy...I don't mind using up other countries' resources and paying them for it, but when we have alternatives like the ANWR reserve available and waste them, well, we've had this debate. Alternatives are already being researched, so I've put this one kind of low on the priority list.
-Tort reform, drugs, epidemics...all kind of low on the grand scheme of things, becuase they tie in with other issues above and aren't as important to me as, say terrorism.
Things I don't think we should spend time on soon : Mother Nature because I don't think we can do anything worse to her than she's already done to herself at some point, and it's a conspiracy anyway; our reputation because it's futile to try to change it since jealosy is a major cause of it...what happens in the US actually affects other nations, but what happens in many other nations doesn't affect us as much, so we simply don't care. Sad, but true. Also, reparations, because it will never happen, and shouldn't. Race-baiters know it'll never happen, but they continue to use it as a campaigning point anyway, so let's just ignore the issue so they focus on something real and usefull to their supporters, like crime and parentless children, which affect everyone in every race.
Hopefully I said why I think they're important without starting too much debate about the actual issue, but I ramble sometimes.