Defining how human immunodeficiency virus (HIV) interacts with macrophages, dendritic cells (DC), and other non-T cell reservoirs remains a critical area of research despite widespread use in the developed world of highly active antiretroviral therapy. In fact, as highlighted at the Fifth International Workshop on HIV and Cells of Macrophage/Dendritic Lineage and Other Reservoirs, as viral suppression in T cells becomes increasingly effective, these alternative reservoirs may take on even greater relative importance as sites for viral persistence and as a target for purging. These cells may be especially important reservoirs in several critical settings of clinical relevance, and there are major differences in the molecular mechanisms that regulate HIV replication in these cells compared with T cells. Dysfunction of these cells may also play a major role in particular aspects of pathogenesis. Three broad themes emerged from the workshop regarding areas of recent progress, which also serve to identify current research challenges of (i). determining the role played by macrophages, DC, and other non-T cell viral targets in transmission and dissemination and as viral reservoirs at various stages of disease and in different compartments in vivo; (ii). identifying the molecular mechanisms by which virus-cell interactions affect the inflammatory, immune, and other functions of these cells; and (iii). defining the unique pathways that regulate infection and replication in these cellular compartments. This issue of JLB contains several reviews and original reports resulting from the workshop that address recent progress and highlight the current research questions regarding these cell types.