Parasitic nematodes release a wide variety of immunomodulatory proteins, which allow them to escape the host's immune-mediated killing or ejection mechanisms. This immunomodulation is mediated by nematode excretory/secretory (E/S) products, which contain multiple families of immunomodulatory proteins. Many of these families are conserved across different parasitic nematodes, while others are apparently unique to specific species. While some E/S products interact with host proteins, others have evolved to target host lipids, glycans, and metabolites. In this review, we will focus on three families of immunomodulatory proteins, which are particularly expanded in intestinal nematodes: the venom allergen-like proteins, the apyrases, and the complement control protein domain-containing proteins. These families of proteins suppress host immune responses, and evidence is gathering that these could be effective vaccine antigens against these intractable parasites.