Antiretroviral agents target specific steps in the HIV replication cycle. This chapter focuses on HIV DNA integration, a step catalyzed by the integrase enzyme. Appreciating the structure of this enzyme and its mechanism of action is vital to understanding how the drugs inhibit this step. The integrase enzyme constitutes vital domains and amino acids that can be drug targets during 3' processing (3'-P) and strand transfer (ST). Active against these processes are some derivatives of Diketo Acids (DKA), Strylquinolones (SQL) and Phenyldipyrimidine (PDP). To date, three drugs active against strand transfer – Raltegravir, Elvitegravir and Dolutegravir – have been approved by the Food and Drug Authority (FDA). Several other agents are still undergoing pre-clinical and clinical trials. Integrase inhibitors are effective against HIV1 and HIV2, including multidrug resistant strains of HIV1. Therefore antiretroviral combinations containing these drugs are effective as first or second line regimens. Resistance to integrase inhibitors mainly follows amino acid substitutions in the catalytic core domain of the enzyme. Y143C/R, Q148H/K/R and N155H mutations have been attributed to Raltegravir and Elvitegravir resistance. These mutations, however, have minimal effect on the action of Dolutegravir.