In this review, the evolution of QSAR is traced from the insightful observations of Crum-Brown and Frazier to Hammetts critical equations and finally Hanschs seminal contributions on hydrophobicity and modelling of biological activity based on extrathermodynamic principles. Todays QSAR models can stand alone, augment other graphical approaches or be examined in tandem with equations of a similar mechanistic genre to truly reveal the power of the paradigm. This review will focus on the three standard classifications routinely used in QSAR analysis - electronic, hydrophobic, and steric, as well as topological indices. Electronic parameters will focus on Hammett sigma constants and their numerous variations. Dipole moments, hydrogen bond descriptors and quantum chemical indices as well as applications of their utilization will be described. The hydrophobicity parameter will be examined by tracing its early history, its operational definition and its determination by either experimental methods or computational calculations. Steric parameters, which run the gamut from size to shape, will be described by Tafts, Hancocks, Chartons, Fujitas, Verloops and Simons contributions. Topological effects, delineated by connectivity indices, kappa shape and electrotopological indices of Kier and Hall are also described. Examples of QSAR models incorporating most of these parameters are reviewed. In cases where the 95% confidence intervals of variables are available, they are listed in parentheses. A brief Comparative QSAR analysis of non-nucleoside reverse transcriptase inhibitors (NNRTIs) is outlined and various models obtained by different groups examining 4, 5, 6, 7-tetrahydro-5- methylimidazo [4, 5,1-j,k][1,4] benzodiazepin-2(1H)-ones (TIBO) and 1-[(2-hydroxyethoxy)methyl]-6- (phenylthio)-thymine (HEPT) derivatives are compared for mechanistic insight that could be useful in the process of inhibitor design.