Despite substantial progress that has been made in understanding many aspects regarding biology and pathogenesis of human immunodeficiency virus type 1 (HIV-1), there is currently no vaccine or curative treatment available. HIV-1 continues to be a major global health problem. In this regard, new strategies are required for promoting a complete immune reconstitution and eradicating the virus from the body. The rationale for the use of hematopoietic stem cell (HSC)-based gene therapy against HIV infection is that, after transplantation, genetically modified HSCs carrying anti-HIV transgenes would engraft, divide and differentiate into large numbers of mature myeloid and lymphoid cells that express antiviral genes and thus are protected from HIV invasion or productive replication. HIV-1 attachment to susceptible cells involves binding of gp120 to CD4 receptor and subsequently to a HIV co-receptor, either CCR5 or CXCR4. The pivotal role of CCR5 in HIV-1 acquisition and disease progression has been established by the discovery of a naturally occurring 32-bp deletion in CCR5 (CCR5Δ 32) which generates a nonfunctional gene product. Homozygosity for CCR5Δ32 confers profound resistance against HIV infection, and heterozygous mutation that induces a decrease in CCR5 surface expression is associated with lower plasma viral load and delayed progression to acquired immune deficiency syndrome (AIDS). This, together with the fact of R5 dominance during the acute and asymptomatic phase, suggests that CCR5 is an attractive target for HIV gene therapeutics. The present review addresses recent advances of CCR5-targeted HSC gene approaches to treat HIV infection, discusses the future prospects and postulates potential strategies in the field.