The signature feature of systemic dimorphic fungi - a family of six primary fungal pathogens of humans - is a temperature-induced phase transition. These fungi grow as a mold in soil at ambient temperature and convert to yeast after infectious spores are inhaled into the lungs of a mammalian host. Seminal work 20 years ago established that a temperature-induced phase transition from mold to yeast is required for virulence. Several yeast-phase specific genes, identified one-by-one and studied by reverse genetics, have revealed mechanisms by which the phase transition promotes disease pathogenesis. Transcriptional profiling of microarrays built with genomic elements of Histoplasma capsulatum and ESTs of Paracoccidioides brasiliensis that represent partial genomes has identified 500 genes and 328 genes, respectively, that are differentially expressed upon the phase transition. The genomes of most of the dimorphic fungi are now in varying stages of being sequenced. The creation of additional microarrays and the application of new reverse genetic tools promise fresh insight into genes and mechanisms that regulate pathogenesis and morphogenesis. The use of insertional mutagenesis by Agrobacterium has uncovered a hybrid histidine kinase that regulates dimorphism and pathogenicity in Blastomyces dermatitidis and H. capsulatum. Two-component signaling appears to be a common strategy for model and pathogenic fungi to sense and respond to environmental stresses.