Human immunodeficiency virus type 1 (HIV-1) is undoubtedly the primary cause of the acquired immunodeficiency syndrome (AIDS), which is a slow, progressive and degenerative disease of the human immune system. The pathogenesis of HIV-1 is complex and characterized by the interplay of both viral and host factors. Practically every stage in the viral life cycle and every viral gene product is a potential target. Although HAART has made long-term suppression of HIV a reality, drug resistance, drug toxicity, drug penetration, adherence to therapy, low levels of continued viral replication in cellular reservoirs and augmentation of host immune responses are some of the most important challenges that remain to be sorted out. Novel targets for the management of HIV infection have become increasingly relevant in view of extensive drug resistance, side effects and high pill burden of some of the conventional anti-retroviral agents. These agents include chemokine receptor antagonists, integrase inhibitors, maturation inhibitors, zinc finger inhibitors, pharmacological CDK inhibitors, Tate-TAR interaction inhibitors, anti-CD4 monoclonal antibodies and antisense oligonucleotides. In this review we gave a basic overview of the virology of HIV-1 including the functions of the different HIV-1 proteins required for effective viral replication, various obstacles to HIV therapy, perspectives related to the issues that are critical in determining the success or failure of HAART, current methods for detecting HIV-1 drug resistance and various novel targets for the management of HIV infection.