PURPOSE OF REVIEW: This review describes how advances in CyTOF and high-dimensional analysis methods have furthered our understanding of HIV transmission, pathogenesis, persistence, and immunity. RECENT FINDINGS: CyTOF has generated important insight on several aspects of HIV biology: (1) the differences between cells permissive to productive vs. latent HIV infection, and the HIV-induced remodeling of infected cells; (2) factors that contribute to the persistence of the long-term HIV reservoir, in both blood and tissues; and (3) the impact of HIV on the immune system, in the context of both uncontrolled and controlled infection. CyTOF and high-dimensional analysis tools have enabled in-depth assessment of specific host antigens remodeled by HIV, and have revealed insights into the features of HIV-infected cells enabling them to survive and persist, and of the immune cells that can respond to and potentially control HIV replication. CyTOF and other related high-dimensional phenotyping approaches remain powerful tools for translational research, and applied HIV to cohort studies can inform on mechanisms of HIV pathogenesis and persistence, and potentially identify biomarkers for viral eradication or control.