Like other complex, multifaceted interventions in medicine, meditation represents a mixture of specific and not-so-specific elements of therapy. However, meditation is somewhat unique in that it is difficult to standardize, quantify, and authenticate for a given sample of research subjects. Thus, it is often challenging to discern its specific effects in order to satisfy the scientific method of causal inferences that underlies evidence-based medicine. Therefore, it is important to consider the key methodological challenges that affect both the design and analysis of meditation research. The goal of this paper is to review those challenges and to offer some practical solutions. Among the challenges discussed are the mismatches between questions and designs, the variability in meditation types, problems associated with meditation implementation, individual differences across meditators, and the impossibility of double-blind, placebo-controlled meditation studies. Among the design solutions offered are aptitude x treatment interaction (ATI) research, mixed quantitative-qualitative methods, and practical (pragmatic) clinical trials. Similar issues and solutions can be applied more generally to the entire domain of mind-body therapies.