Simulation of the correct side chain conformations of amino acid residues is an intriguing issue not only for computational biology, but also for practical outcomes in biotechnology and medicine. This is also a main challenge for molecular simulations, since even in the homology modelling strategy (which uses templates to predict the unknown structure of a protein), the conformation of a side chain generally cannot be easily deduced from the structure of the template. It is important also for applications such as molecular design and docking. Moreover, the correct simulation of the effects of amino acid mutations occurring in many genetic diseases may help in understanding the molecular mechanisms that underlie those pathologies. This review aims to summarize the different strategies developed to predict side chain conformations in proteins. In the current review, differences in approaches are discussed and problems are analyzed, as well as parameters and criteria to compare and evaluate performances of the programs.