Adaptation to environmental conditions is key to fungal survival during infection of human hosts. Although the host immune system is often considered the primary obstacle to fungal colonization, invading fungi must also contend with extreme abiotic stresses. Recent work with human pathogenic fungi has uncovered systems for detecting and responding to changes in temperature, carbon source, metal ion availability, pH, and gas tension. These systems play a major role in adaptation to the host niche and are essential factors for persistence in a mammalian host. Future investigations into fungal responses to these and other abiotic components of the host environment have the potential to uncover novel targets for anti-fungal therapy.