The establishment of the National Center for Complementary and Alternative Medicine (NCCAM) in 1998 as a part of the National Institutes of Health was catalyzed by the increasing interest and use of complementary and alternative medicine (CAM) modalities by the public. This article presents an overview of CAM, summarizes similarities and differences between the regulatory requirements for drugs and CAM/botanical products, identifies several challenges and opportunities for conducting research to demonstrate the safety and efficacy of CAM therapeutics, and highlights the role of NCCAM in supporting and stimulating research in this area.