The chemical signals of mammalian skin that stimulate the secretion of acetabular gland contents of Schistosoma mansoni cercariae were determined by exposing cercariae to fractions of human and pig skin surface obtained by thin-layer chromatography. Postacetabular gland secretion was stimulated by hydrophilic skin extracts but was often combined with a secretion of preacetabular glands. Secretion of preacetabular glands, which contain enzymes for skin lysis, could be selectively stimulated with skin surface lipids. Two different mechanisms of lipid-stimulated preacetabular gland release could be distinguished. First, secretion in combination with penetration behavior and probably tegument transformation was stimulated by the fraction of free fatty acids. Second, secretion independent of penetration behavior and tegument transformation was exclusively stimulated by glucosylceramides and phospholipids, probably phosphatidylcholines. The secretion mechanisms seem to allow a continuous lysis of epidermal macromolecules during the skin passage of the cercariae. Free fatty acids occur in the uppermost skin layers and may stimulate the combination of the first response; phospholipids and glucosylceramides are restricted to deeper epidermal layers and may stimulate the enzyme secretion there. An active preacetabular gland release was also stimulated by toxic chemicals, which could suggest an emergency penetration program for impaired cercariae.