[4][5] After graduating from Yale, he worked briefly as a staff assistant for Senator Richard Schweiker (R-PA) and as a demonstration program evaluator for two non-profit organizations.

[2] He then served as Counselor to the Commissioner of the Social Security Administration from 1986 to 1988 where he led the agency's efforts to end its controversial policy of “nonacquiescence” to certain federal court decisions.

In that capacity he served briefly as White House Ethics Officer, oversaw litigation responses related to the Iran-Contra affair, and drafted the first operations plan for the 25th Amendment.

[7][8] President Bush nominated him for General Counsel of the U.S. Department of Health and Human Services in June 1989 and the Senate unanimously confirmed him later that month.

[2] As General Counsel, Astrue personally tried and won the first federal HIV discrimination enforcement suit,[9] he personally argued and won the first patient dumping enforcement suit,[10] and co-authored with David M. McIntosh the first accelerated drug approval regulation targeted for treatments for fatal diseases for which there was no significant treatment.

[15][2] In 2001-2002 he was considered President Bush's top choice for Food and Drug Administration Commissioner but faced opposition from Senate Democrats because of his industry experience.

[17] In twenty-six months as chief executive officer he engineered one of the most successful turnarounds in biotechnology history and then lost control of the company to Shire Pharmaceuticals in a controversial hostile takeover.

[26] In August 2013, Astrue stepped into the interim CEO position at InVivo Therapeutics, a failing biotech company whose founder/CEO, Frank Reynolds, would later face criminal charges.

[31][32] In the June 2010 issue of First Things, Paul Mariani disclosed that Astrue had been publishing original and translated poetry for many years under the pseudonym of A. M. Juster, an anagram of M. J.

In 2002 Rachel Hadas selected his book of original poetry and translations, The Secret Language of Women, as the winner of the 2002 Richard Wilbur Award.