HIV disproportionately impacts populations that have traditionally suffered from health disparities; thus, it is unsurprising that health disparities are a major driver of the ongoing HIV epidemic in the United States. High rates of HIV prevalence and incidence are now seen in the Southern United States and among black men who have sex with men, transgender women, and individuals in low-income settings. In addition, substance use continues to be a major driver of the HIV epidemic and impacts care outcomes. Efforts at reducing HIV transmission must include focus on engagement and retention in care among individuals at risk of being lost to care. This requires particular emphasis on understanding and addressing patient needs and removing structural barriers to engagement in care. This article summarizes a presentation by Carlos del Rio, MD, at the IAS-USA continuing education program, Improving the Management of HIV Disease, held in New York, New York, in March 2016.