Parasitic nematodes infect a variety of organisms including insects and vertebrates. To survive, they evade host immune responses to cause morbidity and mortality. Despite the vast clinical knowledge regarding nematode infections and their biological makeup, molecular understanding of the interactions between host and parasite remains poorly understood. The utilization of model systems has thus been employed to help elucidate the molecular interactions of the host immune response during parasitic nematode infection. Using model systems, it has been well established that parasitic nematodes evade host immunity by releasing excretory/secretory proteins (ESPs), which are involved in immunomodulation. Model systems have enabled researchers to characterize further the underlying mechanisms ESPs use to facilitate evasion and modulation of the host immune response. This review assessed notable ESPs from parasitic nematodes that infect vertebrates or insects and have been studied in mechanistic detail. Being able to characterize how ESPs affect the immune systems of hosts on a molecular level increases our understanding of host–parasite interactions and could lead to the identification of novel therapeutic targets and important molecular pathways.