HIV infection is a major challenge to mankind and a definitive cure or a viable vaccine for HIV is still elusive. HIV-1 is constantly evolving and developing resistant against clinically used anti-HIV drugs thus posing serious hurdles in the treatment of HIV infection. This prompts the need to developed new anti-HIV drugs; preferentially adopting intelligent ways to counteract an evolving virus. Highly Active Anti-Retroviral Therapy (HAART): a strategy involving multiple targeting through various drugs has proven beneficial in the management of AIDS. However, it is a complex regimen with high drug load, increased risk of drug interactions and adverse effects, which lead to poor patient compliance. Reverse transcriptase (RT) and Integrase (IN) are two pivotal enzymes in HIV-1 lifecycle with high structural and functional analogy to be perceived as drug-able targets for novel dual-purpose inhibitors. Designed multi-functional ligand (DML) is a modern strategy by which multiple targets can be exploited using a single chemical entity. A single chemical entity acting on multiple targets can be much more effective than a complex multi-drug regimen. The development of such multifunctional ligands is highly valued in anti-HIV drug discovery with the proposed advantage of being able to stop two or more stages of viral replication cycle. This review will encompass the evolution of the RT-IN dual inhibitory scaffolds reported so far and the contribution made by the leading research groups over the years in this field.