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Talaromycosis (Penicilliosis) is an opportunistic mycosis caused by the thermally dimorphic fungus <i>Talaromyces</i> (<i>Penicillium</i>) <i>marneffei</i>. Similar to other major causes of systemic mycoses, the extent of disease and outcomes are the results of complex interactions between this opportunistic human pathogen and a host’s immune response. This review will highlight the current knowledge regarding the dynamic interaction between <i>T. marneffei</i> and mammalian hosts, particularly highlighting important aspects of virulence factors, intracellular lifestyle and the mechanisms of immune defense as well as the strategies of the pathogen for manipulating and evading host immune cells.