By the 1980s, Folkman's team turned its attention to the search for molecules that could turn off angiogenesis in tumors. This was a daunting task: no such molecules were known, and few scientists believed they even existed.

The first angiogenesis inhibitor to be identified was interferon-alpha, a natural protein in the body known for its antiviral activity. Bruce R. Zetter, Ph.D., in Folkman's lab showed in the early 1980s that interferon-alpha could also stop endothelial cells from moving and migrating toward a tumor; other scientists then showed the protein's anti-angiogenic activity. Interferon-alpha entered clinical trials for the treatment of life-threatening hemangiomas (masses of blood capillaries) in children in 1989. Folkman and Children's Hospital colleagues Alan Ezekowitz, M.B., Ch.B., D.Phil., now Chief of Pediatrics at the MassGeneral Hospital for Children, and John B. Mulliken, M.D., now director of the Craniofacial Center at Children's Hospital, developed the most extensive clinical experience with this new anti-angiogenic therapy for children. Interferon-alpha is now used in children's hospitals worldwide for severe hemangiomas that fail to respond to conventional therapy, and other anti-angiogenic therapy, has recently been used for severe hemangiomas.

Other early angiogenesis inhibitors from Folkman's lab included: