Well-designed randomized controlled clinical trials assessing treatments in the field of physical medicine and rehabilitation are essential for evidence-based patient care. However, there are challenges unique to clinical trials in physical medicine and rehabilitation due to complex health interventions in this field. We highlight routinely encountered empirical challenges and provide evidence-based recommendations on statistical and methodological approaches for the design and conduct of randomized controlled trials. Some of the issues addressed include challenges with blinding treatment groups in a rehabilitation setting, heterogeneity in treatment therapy, heterogeneity of treatment effects, uniformity in patient-reported outcome measures, and effect on power with varying scales of information. Furthermore, we discuss challenges with estimation of sample size and power, adaption to poor compliance with treatment and missing outcomes, and preferred statistical approaches for longitudinal data analysis. Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME. Upon completion of this article, the reader should be able to: (1) Appraise the complexities of interventions in physical medicine and rehabilitation and how these challenges impact the conduct of clinical trials; (2) Develop an analytical strategy for poor treatment compliance and missing outcomes that can compromise the causal effect sought in a randomized clinical trial; and (3) Recognize the role of a data and safety monitoring board in a clinical trial. Advanced. The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s) ™. Physicians should only claim credit commensurate with the extent of their participation in the activity.