Paracoccidioidomycosis, the most prevalent deep mycosis of Latin America, is caused by Paracoccidioides spp., pleomorphic fungi which are present as multibudding yeast cells in infected tissues. Due to their importance to the region, these fungi and their related disease have been the subjects of intense research for over 50 years. The present chapter is an attempt to summarize the findings of those decades of research and clinical findings, with an update on the latest advances on taxonomy studies, species distribution and reproductive modes, diagnosis trends, virulence factors, as well as clinical manifestations, and updated treatment of the disease.