Cellular viral reservoirs and anatomic sanctuary sites allow continuing HIV-1 replication in patients with suppressed plasma viremia who are receiving highly active antiretroviral therapy and prevent eradication of HIV-1 by these regimens. Cells of macrophage lineage, including monocytes subsets within the blood, play a role in HIV-1 persistence. Evidence of sequence evolution in blood monocytes, in comparison to resting CD4+ T cells, demonstrates their distinct contribution to plasma viremia. There is evidence to suggest that a specific monocyte subset, of CD14loCD16hi phenotype, is more susceptible to HIV-1 infection than the majority of blood monocytes. Trafficking of monocytes through various tissues following their emigration from the bloodstream allows these cells to differentiate into tissue macrophages, or potentially to egress from the tissues as migratory dendritic cells. This review provides an evaluation of the contribution of monocytes to HIV-1 persistence and the HIV-1 reservoir, essential for the effective design of therapeutic eradication strategies.