THE superfamily of low molecular mass GTP-binding proteins, for which the ras proteins are prototypes, has been implicated in the regulation of diverse biological activities including protein trafficking, secretion, and cell growth and differentiation^1–3. One member of this family, CDC42H_s (originally referred to as G_p or G25K)_4,5, seems to be the human homologue of the Saccharomyces cerevisiae cell-division-cycle protein, CDC42S_c(refs ^6–9). A second S. cerevisiae protein, CDC24 (ref. 10), which is known from complementation studies to act with CDC42S_c to regulate the development of normal cell shape and the selection of nonran-dom budding sites in yeast, contains a region with sequence similarity to the dbl oncogene product^11–14. Here we show that dbl specifically catalyses the dissociation of GDP from CDC42H_sand thereby qualifies as a highly selective guanine nucleotide exchange factor for the GTP-binding protein. Although guanine nucleotide exchange activities have been previously described for other members of the Ras-related GTP-binding protein family^15–17, this is the first demonstration, to our knowledge, of the involvement of a human oncogenic protein in catalysing exchange activity.