Homelessness affects more than 580,000 Americans on any given night. Risk factors for homelessness include extreme poverty, substance use, and mental illness. People experiencing homelessness are likely to have multiple chronic medical or mental health conditions. Homelessness increases morbidity associated with cardiovascular, respiratory, and infectious diseases and all-cause mortality. A trauma-informed approach to the examination of people experiencing homelessness is imperative because previous exposure to physical or sexual trauma is common in this population, especially among women. Considerations for medical management include simplifying medication regimens, providing safe options for medication storage, and addressing environmental exposures. A multidisciplinary approach that includes pharmacists, case managers, and social workers improves chronic disease outcomes. Housing First initiatives decrease emergency department use and hospitalizations, and colocating primary care visits with shelters increases overall health care access.