With almost 40 million people infected with human immunodeficiency virus (HIV), it is one of the most devastating diseases with no cure in sight. Over the past two decades, significant progress has been made to identify and validate drug targets for HIV. However, most of the 20 FDA approved drugs are targeted to two enzymes; reverse transcriptase and protease. Other drug targets derived from HIV and host factors are being validated, and novel compounds are being developed to overcome drug resistance. Recent data indicate that low and residual virus found in tissues of the lymphoid and central nervous system (CNS) is likely due to insufficient drug levels. Thus, improvement in the delivery of anti-HIV drugs to these tissues with limited drug penetration or accumulation, is equally important to maximally suppress viral replication. Novel lipid associated drugs (i.e. indinavir) targeted to the lymphoid tissue have been shown to overcome limited drug exposure in the lymph nodes and to further reduce residual virus in tissue. This review discusses viral and cellular targets that could interrupt viral replication, as well as novel and proven strategies to enhance the delivery of anti-HIV drugs to the lymphoid, CNS, and cells where low viral replication and limited drug levels exist.