Tilghman became the second female president in the Ivy League when she took over at Princeton in 2001. Judith Rodin preceded her at the University of Pennsylvania by two weeks and Ruth Simmons followed her two weeks later at Brown.
In an email to Princeton faculty, students and staff, Tilghman said there is a "natural rhythm to university presidencies," The New York Times reported.
A molecular biologist, Tilghman served on the selection committee that chose her. Her colleagues voted on her when she left a meeting early to teach.
During her tenure, Tilghman was a successful fundraiser, bringing in $1.88 billion in a capital campaign during an economic slump. Princeton expanded aid to low- and middle-income students and began several additions to its campus.
"I began to think about what I had set out to do as president and what remained to be done. I concluded somewhat immodestly that every important initiative I set in motion was either concluded -- done -- or was now on an irreversible path to success where it really wouldn't require a lot of my time or attention to ensure that it would be fully realized," she told the Times in an interview.
Tilghman plans to remain on the Princeton faculty, returning to teaching after a sabbatical.
A native Canadian, Tilghman graduated from Queen's University in Kingston, Ontario. She earned a doctorate at Temple University in Philadelphia.