The ability of HIV to mutate and replicate in the presence of antiretroviral therapy (ART) drugs are called HIV drug resistance. There are many reasons for HIV drug resistance happening. Some determinants are related to virus such as infidel reverse transcriptase, error-prone replication, etc. The appearance of drug resistance mutations and viral evolution could be a result of continuing HIV-1 replication in ART among some infected subjects. A wide range of mechanisms has been described with difference characteristics for different classes of drugs and also for drugs of a given class. New antiretroviral (ARV) drugs which are often applied in treatment-experienced patients include the entry inhibitor (Enfuvirtide), protease inhibitors (PIs) (Darunavir and Tipranavir), a C-C chemokine receptor (CCR) type 5 antagonist (Maraviroc), an integrase inhibitor (Raltegravir) and a non-nucleoside reverse transcriptase inhibitor (NNRTI) (Etravirine). The overwhelming data presented in journals and at scientific meetings helps staying informed about current issues, but makes new developments a daunting task.