In this issue of the JCI, the observation of the altered pathogenicity of a Cryptococcus neoformans glucosylceramide (GlcCer) mutant shines new light on the initiation of cryptococcal infection. Rittershaus and colleagues demonstrate that the cell surface glycosphingolipid GlcCer is essential for the fungus to grow in the extracellular environments of the host bloodstream and alveolar spaces of the lung, which, in contrast to the acidic intracellular environment of macrophages, are characterized by a neutral pH (see the related article beginning on page 1651). Their findings establish an unexpected connection between this glycosphingolipid and the fungal responses to physiological CO2 and pH. They also focus new attention on the therapeutic potential of anti-GlcCer antibodies found in convalescent sera.