Schistosomiasis, caused by parasitic helminths, remains a serious human disease in the tropics. Cercariae of Schistosoma mansoni infect their hosts by direct skin penetration, aided by secretions from acetabular and head glands. Both proteolytic and immunomodulatory properties have been ascribed to the released material, but to date only five isoforms of elastase and one putative anti-inflammatory protein (Sm16) have been cloned. We analysed secretions from mechanically transformed cercariae by two-dimensional electrophoretic separation. An average gel image was created and compared it to a separation of soluble larval extract, revealing a less complex spot pattern in the secretions, with 60% of the spots matched to the larval extract. Subsequent tandem mass spectrometric analysis identified 48 spots from the released material, representing approx. 80% of its normalised volume. Twenty-nine of these are likely to originate in the vesicles and 18 in the cytosol of the glands (the latter class being present due to holocrine secretion); one is unknown. The vesicular proteins were significantly more enriched than the cytosolic proteins in the released material, when compared to the larval extract. A novel metalloproteinase (termed SmPepM8) was the second most abundant constituent after three isoforms of cercarial elastase. In addition, a dipeptyl peptidase IV (SmDPP IV) was discovered, but in much smaller quantity. A new serine protease inhibitor (SmSerp_c) was also prominent. Along with Sm16, four potential immunomodulators were identified, three with similarity to venom allergens (SmSCP_a, b and c) and one with homology to the potassium-channel blockers in scorpion venom (SmKK7). Interrogation of the EST database found transcripts encoding the majority of vesicular proteins present solely in the intramolluscan stages of the life-cycle. Distinct patterns of radiolabel incorporation suggested three separate origins for the vesicular proteins. All the novel constituents merit investigation as vaccine candidates, and the potential immunomodulators as therapeutic agents.