Clinical and epidemiologic investigations are paying increasing attention to the critical constructs of "representativeness" of study samples and "generalizability" of study results. This is a laudable trend and yet, these key concepts are often misconstrued and conflated, masking the central issues of internal and external validity. The authors define these issues and demonstrate how they are related to one another and to generalizability. Providing examples, they identify threats to validity from different forms of bias and confounding. They also lay out relevant practical issues in study design, from sample selection to assessment of exposures, in both clinic-based and population-based settings.