Spider silk is a fascinating material combining remarkable mechanical properties with low density and biodegradability. Because of these properties and historical descriptions of medical applications, spider silk has been proposed to be the ideal biomaterial. However, overcoming the obstacles to produce spider silk in sufficient quantities and in a manner that meets regulatory demands has proven to be a difficult task. Also, there are relatively few studies of spider silk in biomedical applications available, and the methods and materials used vary a lot. Herein we summarize cell culture- and in vivo implantation studies of natural and synthetic spider silk, and also review the current status and future challenges in the quest for a large scale production of spider silk for medical applications. © 2011 Wiley Periodicals, Inc. Biopolymers 97: 468–478, 2012.