Host defense against pathogens involves various receptors expressed in cells of the immune system. Upon pathogen recognition, these proteins mediate a plethora of effector functions, such as the secretion of key protective cytokines and other immune mediators. These receptors include C-type lectins (CTLs), which are increasingly being recognized as major players in the host response to microbes. One particular CTL, DCSIGN/CD209, recognizes conserved sugar motifs in a number of viruses, parasites and bacteria. In particular, we and others have shown that DC-SIGN plays an important part in the recognition by dendritic cells and macrophages of Mycobacterium tuberculosis, the causal agent of tuberculosis in humans. Using the mouse as a model: host for M. tuberculosis, we recently showed that the DC-SIGN homologue SIGNR3 mediates protection against the tubercle bacillus, possibly through secretion of the key cytokines interleukin 6 and tumor necrosis factor. Here, we summarize and discuss these findings and their implications for the design of future studies aiming to improve our understanding of the role of DC-SIGN and other C-type lectins in immunity to mycobacteria and other pathogens.