Despite the key position of reptiles in evolutionary history, reptilian immune responses have received relatively little attention. Like all jawed vertebrates, reptiles possess both an innate and adaptive immune system to recognize unknown foreign substances. Although diverse immunological mechanisms have been discovered, they seem not to be adequate to avoid the invasion of some microorganisms and stop some infections. All species of crocodilians show well-defined social behaviors, and hierarchical dominance attitudes can be observed in both males and females. This behavior generates conflicts that are expressed through aggression and combat with serious health consequences. These animals have evolved a very active immune mechanisms and components that provides a fast and effective line of defense. Science has focused on those mechanisms and components because crocodilians are an especially interesting group on which to perform evolutionary studies because they are one of the surviving archosaurs, which represents an important link within “higher” vertebrates. Based on those background, they are being observed and evaluated for their potential application in domestic and wild species. These findings will not only generate an increasing value as a therapeutic resource but also to the ecosystem, and to decode biological processes that could lead to phylogenetic (ancestral) cognition. In this review, many components of the crocodilian immune system are described that could lead to a more thorough understanding of how these animals select the most appropriate response to environmental challenges and antigen exposure and identify networks to study and interesting opportunities to the experts in the field.