Inclusion of underrepresented groups in clinical trials is important for several reasons. Age, sex, race, genetic factors, concomitant use of other medications, and comorbid conditions all may play pivotal roles in response to a drug or intervention. Despite the legislation for broader inclusion of underrepresented groups in clinical trials (via the National Institutes of Health [NIH] Revitalization Act of 1993), underrepresentation of particular populations, particularly minorities, continues to be a problem. Studies of predictors of clinical trial enrollment suggest that most people participate in clinical research to find relief from a disease, not for financial remuneration. Yet, men and whites are more likely to enroll in studies and some data indicate that certain patient populations are preferentially (albeit sometimes inadvertently) chosen for study enrollment. This tendency toward inclusion stems from human nature—the natural tendency for an investigator to relate to a particular investigative topic due to a special connection based on a cultural, socioeconomic, age, ethnicity, or gender level. This article reviews the most common population issues for clinical studies: age, gender, race, socioeconomic status, comorbidities, and disease severity, with examples of each from published studies. Recommendations are also offered to overcome these barriers.