The osteopathic profession has been challenged over the past decade to provide clinically relevant research. The conduct of evidence-based osteopathic research is imperative not only for scientific, economic, and professional reasons, but also to drive health care policy and clinical practice guidelines. This paper summarizes recent studies in response to the osteopathic research challenge, including clinical trials registered with ClinicalTrials.gov and a systematic review and meta-analysis of osteopathic manipulative treatment (OMT) for low back pain. The concept of the OMT responder is introduced and supported with preliminary data. Within the context of a pain processing model, consideration is given to genomic (e.g., the catechol-O-methyltransferase gene) and psychological (e.g., depression and somatization) factors that are associated with pain sensitivity and pain progression, and to the role that such factors may play in screening for OMT responders. While substantial progress has been made in osteopathic research, much more needs to be done.