In Candida albicans, three putative histidine kinase genes have been described thus far, including CaSLN1, CaNIK1/COS1 and CaHK1. The encoded proteins for C. albicans, CaSln1p and CaNik1p, which are similar to Sln1p from Saccharomyces cerevisiae and Nik-1 from Neurospora crassa, seem to function in osmoregulation and morphogenesis, respectively. Recently, the isolation of CaHK1, a putative histidine kinase gene from C. albicans has been reported. In addition to the histidine and aspartyl domains located at its C-terminus as previously described, it is shown here that the N-terminal domain of Cahk1p contains a P-loop motif and a sequence which shows significant homology with the seven C-terminal domains of serine/threonine kinases. The Ser/Thr-homologous domains of Cahk1p could, in fact, correspond to its sensor sequence. CaHK1 has been mapped to chromosome 2 and gene deletion studies were undertaken to understand its function. Deltacahk1 mutants are phenotypically different from any other histidine kinase mutants thus far described either in C. albicans or in any other yeast or filamentous fungus. This study demonstrates that deltacahk1 mutants flocculate extensively in a gene-dosage-dependent manner under conditions which induce germ-tube formation, such as growth in medium 199 (pH 7.5). The flocculation occurs by an interaction along the hyphal surfaces, probably because of the altered expression of one or more hyphal-cell-surface components in the deltacahk1 mutants. These results indicate that CaHK1 could be involved in regulating their expression.