Non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) have become an inherent component of highly active antiretroviral therapy (HAART) in the treatment of human immunodeficiency virus type 1 (HIV-1) infections. One of the most serious problems associated with NNRTIs is that the virus exhibits resistance to the drug through mutation once the virus is exposed to the drug. New inhibitors effective against these mutants and resistant to new mutations are needed in the treatment of HIV-1 infection. Most mutations are such that larger side chain amino acids are replaced with a smaller side chain. Structural and computational approaches have been used to study the interaction between the NNRTI and RT and the dynamics of wild type mutated RT with and without a bound NNRTI to help understand the mechanism of inhibition and NNRTI resistance. It is still not understood how a NNRTI binding in a pocket, 10 A away the polymerase active site, affects the activity of RT, although several hypotheses have been suggested. Therefore, the focus for the development of next generation NNRTIs has to be the design of compounds with an improved resistance profile. Elucidating the mechanism of the interaction between NNRTI and RT is critical if structure-based drug development for HIV-1 RT is to be successful. This calls for a better understanding of the resistance mechanism by crystallographic and computational studies. This review will take a critical look at the numerous computational studies on HIV-RT and compare those results against the current structural and experimental data available.