Health psychology and behavioral medicine are founded on the biopsychosocial model, in which health and disease reflect reciprocal influences among biological, psychosocial, and sociocultural processes. As a result, research methods in these fields draw on concepts and methods from several disciplines and often require their integration. Health psychology and behavioral medicine include three major topics: health behavior and risk reduction; psychosocial aspects of medical illness and medical care; and psychosocial and psychobiological influences on disease. This chapter emphasizes methodological challenges in the third topic, although the issues discussed are broadly relevant to the others. Conceptualization and measurement of health endpoints presents evolving challenges in which measured outcomes must capture specific and well-defined aspects of health and disease. In the identification of psychosocial predictors of health outcomes, psychosocial epidemiology research must address a variety of challenges, including the conceptualization, measurement, and analysis of overlapping risk factors. In research on the psychobiological mechanisms linking risk and resilience factors with health outcomes, theory-driven research should consider a broad range of interrelated physiological processes and multiple sources of pathogenic physiological activation. Across the various research topics, clear ties to conceptual models, consideration of developmental issues across the lifespan, the need to examine both between- and within-person associations in many research questions, and the importance of health disparities and related aspects of ethnic and cultural diversity are important in measurement, design, and analysis of biopsychosocial research.