Glycosylation of proteins has proven extremely important in a variety of cellular processes, including enzyme trafficking, tissue homing and immune functions. In the past decade, increasing interest in carbohydrate-mediated mechanisms has led to the identification of novel carbohydrate-recognizing receptors expressed on cells of the immune system. These non-enzymatic lectins contain one or more carbohydrate recognition domains (CRDs) that determine their specificity. In addition to their cell adhesion functions, lectins now also appear to play a major role in pathogen recognition. Depending on their structure and mode of action, lectins are subdivided in several groups. In this review, we focus on the calcium (Ca2+)-dependent lectin group, known as C-type lectins, with the dendritic cell-specific ICAM-3 grabbing non-integrin (DC-SIGN) as a prototype type II C-type lectin organized in microdomains, and their role as pathogen recognition receptors in sensing microbes. Moreover, the cross-talk of C-type lectins with other receptors, such as Toll-like receptors, will be discussed, highlighting the emerging model that microbial recognition is based on a complex network of interacting receptors.