CARD9 is a caspase recruitment domain-containing signaling protein that is highly expressed in dendritic cells and in macrophages. Work over the last two years has identified CARD9 as a central regulator of innate immunity. Best characterized is CARD9's function downstream of ITAM-bearing or ITAM-coupled receptors in myeloid cells, including its essential role downstream of the antifungal pattern-recognition receptor Dectin-1. In the ITAM receptor pathway, CARD9 couples receptor proximal splenic tyrosine kinase SYK activation to the canonical NF-kappaB pathway. In addition, CARD9 is involved in the activation of p38 and JNK kinases and it can function downstream of cytosolic pattern-recognition receptors. CARD9 signaling mediates mammalian innate immune responses against selected fungi, bacteria, and viruses and can prime and shape adaptive immunity. This review will summarize current knowledge on CARD9 signaling and its function in the innate immune response.