G protein-coupled receptors (GPCRs) represent the largest family of signal transduction membrane proteins and play a critical role in many key physiological processes such as neurotransmission, cellular metabolism, secretion, cell growth, immune defence, and differentiation. Therefore, it is not surprising that these receptors represent a realized and ongoing opportunity for drug development. In this scenario, structure-based drug design techniques turned out to be a really attractive approach, leading to a breakthrough in the discovery of novel therapeutic agents. Indeed, much of this success has to be attributed to the pioneering elucidation of the bovine rhodopsin crystal structure, which represents a milestone in the understanding of GPCRs structures. Starting from the experimentally found rhodopsin 3D coordinates, the tandem application of homology building techniques and molecular docking has become one the most important approaches for structure and ligand binding analysis. Nevertheless, the construction of realistic models of certain GPCRs still remains time consuming and requires many refinements of the models in close association with experiments. This review is aimed at providing a deep view into the current status of GPCR modeling, highlighting the recent progresses made in the rhodopsin-based homology building together with alternative computational approaches. The application of these techniques in the detection of GPCR ligands and the elucidation on how they impact the world of drug discovery is also discussed.