Serum induces Candida albicans to make a rapid morphological change from the yeast cell form to hyphae. Contrary to the previous reports, we found that serum albumin does not play a critical role in this morphological change. Instead, a filtrate (molecular mass, <1 kDa) devoid of serum albumin induces hyphae. To study genes controlling this response, we have isolated theRAS1 gene from C. albicans by complementation. The Candida Ras1 protein, like Ras1 and Ras2 ofSaccharomyces cerevisiae, has a long C-terminal extension. Although RAS1 appears to be the onlyRAS gene present in the C. albicans genome, strains homozygous for a deletion of RAS1(ras1-2/ras1-3) are viable. The Candidaras1-2/ras1-3 mutant fails to form germ tubes and hyphae in response to serum or to a serum filtrate but does form pseudohyphae. Moreover, strains expressing the dominant activeRAS1^V13 allele manifest enhanced hyphal growth, whereas those expressing a dominant negativeRAS1^A16 allele show reduced hyphal growth. These data show that low-molecular-weight molecules in serum induce hyphal differentiation in C. albicans through a Ras-mediated signal transduction pathway.