Pathogenesis in intestinal and urogenital protozoan infections is multifactorial, depending mainly on the balance between parasite virulent molecules and host-induced innate immune responses. With exception of primary amoebic meningoencephalitis (PAM), the majority of these infections are asymptomatic or associated with mild manifestations. In spite of that, these protozoa possess several cysteine proteases (CPs) that are considered as important virulence factors. Several studies showed involvement of CPs in diverse processes resulting in severe pathogenesis and virulence in these protozoa such as mucin degradation, cytoadherence, damage of the tight junctions of the inter-epithelial cells, cytoskeleton disruption, as well as evasion of the host immune response. The present review addresses variable molecular mechanisms dealt with by protozoal CPs to invade host tissue and evade host immune response resulting in disease pathogenesis and parasite virulence. In fact, a better understanding of CPs roles in parasite pathogenesisis useful in identification of novel chemotherapeutic targets and/or development of vaccine candidates to reduce transmission of a wide range of communicable diseases as well as prevention of occurrence of high morbidity diseases such as PAM