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The "presidential line of succession" defines who may become or act as President of the United States upon the incapacity, death, resignation, or removal from office (by impeachment and subsequent conviction) of a sitting president or a president-elect.

-Wikipedia

President-elect Obama doesn't have his entire cabinet picked out yet, but from what he has given us to work with and with some pure speculation on my part, let's take a look at who could possibly become the leader of our nation should something awful happen.
1. President - Barack Obama
2. Vice President - Joe Biden
      The pride of Scranton. Mrs. Biden's baby boy Joe is known for being excessively long-winded in his speeches. He also supports reinstating the Federal Assault Weapons Ban and voted to ban semi-automatic firearms.  
3. Speaker of the House - Nancy Pelosi
      Called for the denouncement of China and voted in favor of keeping the travel restrictions for Americans to Cuba. Pelosi also voted for the use of federal funds (read: taxpayer money) to perform abortions in overseas military facilities. Also among her voting record: FOR the 2008 Bailout, FOR the Patriot Act, For No Child Left Behind, FOR increased Medicaid & Medicare, AGAINST drilling in ANWAR. She is also a supporter of amnesty & rights to illegal immigrants.
4. Secretary of State - Hillary Clinton
      Power hungry Hillary. Universal healthcare. Somehow being the First Lady gives her a lifetime of experience...
5. Secretary of the Treasury - Tim Geithner
      President of the NY Fed, which is an illegal & unconstitutional institution. His grandfather was an adviser to President Eisenhower & coincidentally the vice president of Ford Motor Company. Played a role in the decision to bailout AIG.
6. Secretary of Defense - Robert Gates
      Replaced Rumsfeld in 2006 under Bush. President-elect Obama has offered him the position under the new administration and Gates has supposedly accepted.
7. Attorney General - Eric Holder
      If approved, Holder would be the first black Attorney General. He served under Janet Reno in the Clinton administration.

Following those already mentioned would be the Sec. of the Interior(Sally Jewell/John Kitzhaber), Sec. of Agriculture(Tom Vilsack), Sec. of Commerce (Bill Richardson), and the Secretary of Labor.

I don't think America has ever had to go past the Vice President and since JFK the succession list hasn't been needed at all. But just in case you were wondering... there it is.

ohhhh... Edit!
We had to go to Gerald Ford after Nixon resigned.