Talaromyces (Penicillium) marneffei is a thermally dimorphic fungus that causes talaromycosis, and the pathogen is found throughout tropical and subtropical Asia. T. marneffei has specifically emerged as an opportunistic fungal pathogen in individuals with advanced HIV disease and, to a lesser extent, other immunocompromised conditions, but more recently talaromycosis is increasingly described in immunocompetent people. Due to the high mortality rate of up to 50%, understanding T. marneffei interactions with host immune responses and diagnostic modalities is vital to the development of strategies to reduce morbidity and mortality. In this chapter, we describe T. marneffei virulence factors that enhance the fungus’ capacity for survival and growth in the host to lead to disease. We also discuss approaches for early diagnosis, which are essential to reduce the mortality rate in talaromycosis. Talaromycosis remains a neglected disease, but advances in our understanding of host-pathogen dynamics as well as the ongoing development of new diagnostic approaches are poised to enhance our capacity to combat this disease.