Cysteine proteases play numerous and extremely important roles in the life cycle of parasitic organisms with medicinal importance. From general catabolic functions and protein processing, cysteine proteases may be key to parasite immunoevasion, excystment/encystment, and cell and tissue invasion. Parasite cysteine proteases are unusually immunogenic and have been exploited as serodiagnostic markers and vaccine targets. The research focused on the development of new drugs actives toward this macromolecular target is an important task, where the rational design is considered as a critical step on it. The discovery of new drugs is a complex and multidisciplinary process, which includes an in-depth knowledge of organic chemistry, pharmacology, biochemistry, computer sciences, and others. This process involves high costs and several scientific fields, leading to the necessity to develop new processes that involve optimization of molecular modeling applied to the identification of bioactive molecules. These techniques could increase the probability of obtaining a rational-designed compound, with high activity and safety, which could be considered as a potential drug in the future. Thus, the use of computational techniques has become increasingly common in medical chemistry laboratories due to their low costs and high correlation with experimental results from assays. A broadly used technique in the rational design of active compounds is molecular docking of small ligand at the active site from the biological targets. In this chapter, we will demonstrate in detail different molecular modeling techniques applied to the development of new inhibitors against cruzain (Trypanosoma cruzi); falcipain (Plasmodium falciparum); SmHDAC8 (Schistosoma mansoni); nsP2 (Chikungunya virus) enzymes; and others, such as cathepsin family; caspase family, 3Cpro (Enterovirus 71) and 3CLpro (Coronavirus). Finally, studies have revealed that the application of molecular modeling is a powerful tool for predicting new active and productive molecules against infectious diseases.