Cryptococcus neoformans is an opportunistic fungal pathogen that causes fatal meningoencephalitis in immunocompromised hosts such as patients with AIDS and hematological malignancy. Host defense to C. neoformans infection is mediated by Th1-type cellular immunity, which is triggered by host cell recognition of the pathogen-associated molecular patterns via the pattern recognition receptors. Recently, our study revealed that TLR9-dependent sensing of cryptococcal DNA was a pivotal step in initiating the host defense to this infection and raised a possibility that this process may be triggered in a distinct manner by bacterial DNA with a canonical CpG motif. In addition, we found that mice deficient in CARD9, a critical adapter molecule for signaling via C-type lectin receptors (CLRs), was highly susceptible to cryptococcal infection with impaired immune responses, suggesting a possible involvement of some CLRs. In this article, we review advances in understanding the pattern recognition and host defense response to C. neoformans, with a particular focus on our recent results.