The Rap-pathway has been implicated in various cellular processes but its exact physiological function remains poorly defined. Here we show that the Caenorhabditis elegans homologue of the mammalian guanine nucleotide exchange factors PDZ-GEFs, PXF-1, specifically activates Rap1 and Rap2. Green fluorescent protein (GFP) reporter constructs demonstrate that sites of pxf-1 expression include the hypodermis and gut. Particularly striking is the oscillating expression of pxf-1 in the pharynx during the four larval molts. Deletion of the catalytic domain from pxf-1 leads to hypodermal defects, resulting in lethality. The cuticle secreted by pxf-1 mutants is disorganized and can often not be shed during molting. At later stages, hypodermal degeneration is seen and animals that reach adulthood frequently die with a burst vulva phenotype. Importantly, disruption of rap-1 leads to a similar, but less severe phenotype, which is enhanced by the simultaneous removal of rap-2. In addition, the lethal phenotype of pxf-1 can be rescued by expression of an activated version of rap-1. Together these results demonstrate that the pxf-1/rap pathway in C. elegans is required for maintenance of epithelial integrity, in which it probably functions in polarized secretion. ; The Rap-pathway has been implicated in various cellular processes but its exact physiological function remains poorly defined. Here we show that the Caenorhabditis elegans homologue of the mammalian guanine nucleotide exchange factors PDZ-GEFs, PXF-1, specifically activates Rap1 and Rap2. Green fluorescent protein (GFP) reporter constructs demonstrate that sites of pxf-1 expression include the hypodermis and gut. Particularly striking is the oscillating expression of pxf-1 in the pharynx during the four larval molts. Deletion of the catalytic domain from pxf-1 leads to hypodermal defects, resulting in lethality. The cuticle secreted by pxf-1 mutants is disorganized and can often not be shed during molting. At later stages, hypodermal degeneration is seen and animals that reach adulthood frequently die with a burst vulva phenotype. Importantly, disruption of rap-1 leads to a similar, but less severe phenotype, which is enhanced by the simultaneous removal of rap-2. In addition, the lethal phenotype of pxf-1 can be rescued by expression of an activated version of rap-1. Together these results demonstrate that the pxf-1/rap pathway in C. elegans is required for maintenance of epithelial integrity, in which it probably functions in polarized secretion.