Mucormycosis is a devastating disease and can occur in patients with a variety of risk factors, the most important of which are immunosuppression, anatomic barrier breakdown, iron overload, and hyperglycemia/acidosis. Similarly to what occurs with Aspergillus, the host stimulates an innate immune response against the challenging sporangiospores and invading hyphae of Zygomycetes. This article discusses the host defense to different Zygomycetes, its augmentation, and its subsequent impact on the outcome of mucormycosis.