We are all exposed to fungal organisms daily, and although many of these organisms are not harmful, billions of people a year contract a fungal infection. Most of these infections are not fatal and can be cleared by the host immune response. However, due to an increase in high-risk populations, the global fungal burden has increased, with more than 1.5 million deaths per year caused by invasive fungal infections. The fungal cell wall is an important surface for interacting with the host immune system as it contains pathogen-associated molecular patterns (PAMPs) which are detected as being foreign by the host pattern recognition receptors (PRRs). C-type lectin receptors are a group of PRRs that play a central role in the protection against invasive fungal infections. Following the recognition of fungal PAMPs, CLRs trigger various innate and adaptive immune responses. In this chapter, we specifically focus on C-type lectin receptors capable of activating downstream signaling pathways, resulting in protective antifungal immune responses. The current roles that these signaling CLRs play in protection against four of the most prevalent fungal infections affecting humans are reviewed. These include Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans and Pneumocystis jirovecii.