In recent years, it has become apparent that the lung is an important niche for the proliferation of human immunodeficiency virus (HIV), which may have implications for highly active antiretroviral therapy (HAART). The lung itself is a major site for the opportunistic infections associated with the progression to acquired immune deficiency syndrome (AIDS), specifically Pneumocystis carinii, Myobacterium tuberculosis and pyogenic bacteria. These cases of active pulmonary complications are direct indicators of enhanced progression to AIDS-defining illness and increased morbidity and mortality. It is therefore essential that the interaction between the lung and HIV is fully understood. Recent research indicates the lung may be a major sanctuary for the virus, with distinct evolution and replication in contrast to other target organs for HIV. In this review, we will discuss the recent findings of HIV infection, evolution, host factors involved in the control of HIV within the lung and the impact this may have on current therapy.