Clinical trials are often considered the gold standard of care for cancer treatment. The National Cancer Institute reports less than 3% of adult cancer patients participate in clinical trials and participation rates among certain vulnerable populations (elderly, racial and ethnic minority, rural, and low social economic status patients) are even lower. This chapter focuses on understanding the cancer burden in these identified populations and describing barriers to accrual, followed by effective solutions to addressing barriers in these populations. It uses two frameworks to describe clinical trial accrual in vulnerable populations. First, the Accrual to Clinical Trials framework, which posits that the majority of accrual barriers can be categorized as patient, system, and provider factors that influence or impact accrual to clinical trials. The second framework is Multilevel Model of Health Disparities, which states that disparities interact synergistically to promote reduced access and increased risk of developing and dying from disease.