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. After graduating from law school, he clerked from 1983 to 1984 for U.S. District Court Judge
Walter Jay Skinner. 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. He served until November 1992 and, by virtue of his position, he also had concurrent appointments to the
United States Access Board, which received broad regulatory authority after enactment of the
Americans with Disabilities Act of 1990, and to the
Administrative Conference of the United States. he personally argued and won the first patient dumping enforcement suit, 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. He also was involved in high-profile disputes with
National Institutes of Health Director
Bernadine Healy over the patenting of human DNA sequences of unidentified function and with the state of Oregon's use of polling data about quality of life to deny medications to people with HIV; his positions ultimately prevailed in both disputes. Astrue worked as a partner in the health law department of the Boston law firm of
Mintz, Levin, Cohn, Ferris, Glovsky and Popeo from November 1992 until June 1993 until he joined
Biogen as General Counsel in June 1993. At Biogen he was known for prevailing in multiple lawsuits attempting to block the sale of
Avonex, which became a breakthrough drug for multiple sclerosis, and for obtaining important patent extensions. In 2000 Astrue joined Transkaryotic Therapies as Senior Vice President-Administration and General Counsel. In 2003 he briefly left Transkaryotic Therapies and then returned as chief executive officer. 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. In August 2005, Astrue was named Interim Chief Executive Officer of the failing Epix Pharmaceuticals and orchestrated a merger of the company with
Predix Pharmaceuticals in May, 2006. President Bush nominated Astrue to be Commissioner of Social Security on September 14, 2006. The Senate unanimously confirmed him on February 1, 2007, and he was sworn in on February 12, 2007. He inherited a rapidly growing backlog of disability cases, which he reduced significantly over his six years in office. One of his initiatives in this area was a system called “Compassionate Allowances” which expedites review of claims certain or almost certain to be allowed, often within a matter of days. A list of these qualifying conditions was created too which are all very serious, difficult to live with, and many are considered terminal illnesses. He moved the agency from its longstanding reliance on COBOL toward web-based systems and improved the quantity and quality of the agency's electronic services, which ranked at the top of the public satisfaction surveys of the
American Customer Satisfaction Index. He saw that the agency's fraying computer center would be out of capacity by late 2012 and had no significant backup capacity; he built two new co-equal data centers, one of which became operational during his term and one of which became operational shortly after he left office. During his tenure the time to a hearing dropped to under a year, but then rose quickly after his tenure. Since leaving InVivo, Astrue has focused on his writing (see below) and nonprofit boards. He is currently a board member for the
National Alliance for Hispanic Health and the
Association of Writers and Writing Programs. In 2025, Astrue was the recipient of the Robert M. Ball Award from the National Academy of Social Insurance along with Martin O'Malley for his "leadership, innovation, and dedication to strengthening the Social Security Administration." ==Literary work as A.M. Juster (pseudonym)==