An understanding of the molecular bases of pathogenicity in Blastomyces dermatitidis and related systemic dimorphic fungi has been limited until recent years. Yeast cells of B. dermatitidis display an adhesion promoting protein termed WI-1. Recent studies entailing homologous gene targeting and mutation of WI-1 have provided null mutants at this locus and demonstrated the crucial role of the WI-1 adhesin in pathogenesis of blastomycosis. Ongoing studies are pointing to a link between phase-specific expression of WI-1 and the observation that transition to yeast cells is essential for the acquisition of pathogenicity by B. dermatitidis. Recombinant attenuated yeast that lack WI-1 are serving as invaluable tools for induction of vaccine resistance and are pointing to new insights about adaptive immunity to B. dermatitidis.