Whole systems of healthcare offer unique methodological and theoretical challenges for researchers. Herbalism has its own set of methodological and philosophical research issues that are beyond those presented for whole system research in general. It was our objective to explore various conceptual and methodological issues surrounding whole system herbal research.An International Society for Complementary Medicine Research workshop, Challenges in Herbal Whole System Research, was presented. Starting from a definition of herbalism, the most important challenges to herbal whole system research were elicited with inputs from both the workshop presenters and the audience.Five major challenges unique to herbal whole system research were identified: (1) defining herbalists and herbalism, (2) the role of the natural products industry in herbal research, (3) designing placebos and delivering active herbal treatments as given by herbalists, (4) researching the herb as a living entity, and (5) designing trials to investigate and develop multicomponent herbal therapies.Unique methods and theoretical frameworks are required to design studies of herbalism. Solutions to these methodological challenges need to be addressed to conduct research that examines herbal systems of medicine versus conducting trials on individual herbs given out of their original therapeutic context.