There are several Quantitative Structure-Activity Relationship (QSAR) methods to assist in the design of compounds for medicinal use. Owing to the different QSAR methodologies, deciding which QSAR method to use depends on the composition of system of interest and the desired results. The relationship between a compound's binding affinity/activity to its structural properties was first noted in the 1930s by Hammett and later refined by Hansch and Fujita in the mid-1960s. In 1988 Cramer and coworkers created Comparative Molecular Field Analysis (CoMFA) incorporating the three-dimensional (3D) aspects of the compounds, specifically the electrostatic fields of the compound, into the QSAR model. Hopfinger and coworkers included an additional dimension to 3D-QSAR methodology in 1997 that eliminated the question of "Which conformation to use in a QSAR study?", creating 4D-QSAR. In 1999 Chemical Computing Group Inc. (CCG) developed the Binary-QSAR methodology and added novel 3D-QSAR descriptors to the traditional QSAR model allowing the 3D properties of compounds to be incorporated into the traditional QSAR model. Recently CCG released Probabilistic Receptor Potentials to calculate the substrate's atomic preferences in the active site. These potentials are constructed by fitting analytical functions to experimental properties of the substrates using knowledge-based methods. An overview of these and other QSAR methods will be discussed along with an in-depth examination of the methodologies used to construct QSAR models. Also, included in this chapter is a case study of molecules used to create QSAR models utilizing different methodologies and QSAR programs.