Helminth parasites have large genomes (∼108 bp) which are likely to encode a spectrum of products able to block or divert the host immune response. We have employed three parallel approaches to identify the first generation of 'immune evasion genes' from parasites such as the filarial nematode Brugia malayi. The first strategy is a conventional route to characterise prominent surface or secreted antigens. In this way we have identified a 15-kDa protein, which is located on the surface of both L3 and adult B. malayi, and secreted by these parasites in vitro, as a member of the cystatin (cysteine protease inhibitor) family. This product, Bm-CPI-2, blocks conventional cysteine proteases such as papain, but also the aspariginyl endopeptidase involved in the Class II antigen processing pathway in human B cells. In parallel, we identified the major T cell-stimulating antigen from the microfilarial stage as a serpin (serine protease inhibitor), Bm-SPN-2. Microfilariae secrete this product which blocks two key proteases of the neutrophil, a key mediator of inflammation and innate immunity. The second route involves a priori hypotheses that helminth parasites encode homologues of mammalian cytokines such as TGF-β which are members of broad, ancient metazoan gene families. We have identified two TGF-β homologues in B. malayi, and shown that one form (Bm-TGH-2) is both secreted by adult parasites in vitro and able to bind to host TGF-β receptors. Likewise, B. malayi expresses homologues of mammalian MIF, which are remarkably similar in both structure and function to the host protein, even though amino acid identity is only 28%. Finally, we deployed a third method of selecting critical genes, using an expression-based criterion to select abundant mRNAs taken from key points in parasite life histories. By this means, we have shown that the major transcript present in mosquito-borne infective larvae, Bm-ALT, is a credible vaccine candidate for use against lymphatic filariasis, while a second abundantly-expressed gene, Bm-VAL-1, is similar to a likely vaccine antigen being developed against hookworm parasites.