Not-for-profit or nonprofit organizations (NPOs) are playing an increasingly important role in providing solutions to the significant challenges faced by both large pharmaceutical and smaller biotechnology companies in today's world. NPOs chartered for the public benefit are common in the United States and in selected other parts of the world. The largest NPOs in the U.S. with bioscience programs include Battelle, the Midwest Research Institute, the Research Triangle Institute, Southern Research, and SRI International. To provide a perspective on NPO business models, 10 SRI case studies spanning a broad range of technical and business initiatives are summarized herein, including basic and contract research, discovery of new drugs and biologics, pharmaceutical and biotech R&D services, technology pivots, company spin-ins and spin-outs, and the creation of new NPOs. The article concludes with lessons learned and food for thought for both pharmaceutical companies and outsourcing participants. Drug Dev Res 70 : 461-471, 2009.