The human immune response during coccidioidomycosis is intimately involved with the development of delayed-type hypersensitivity and cellular immunity. Sixty percent of those infected have no symptoms and benign outcome is generally associated with a specific cellular immune response to coccidioidal antigens. We have recently teased out the human pulmonary granulomatous response during coccidioidomycosis and noted that there are perigranulomatous clusters of lymphocytes consisting predominantly of B lymphocytes and CD4(+) T lymphocytes. In other work, we have found that the mannose receptor as well as the toll-like receptors TLR2 and TLR4 may have a role in recognizing glycosylated coccidioidal antigens. In addition, the IL-12 receptor axis appears to be operative during antigen recognition and IL-12p40 may be the active moiety. Finally, peripheral blood mononuclear cells from persons with disseminated coccidioidomycosis are able to respond to coccidioidal antigen when it is presented by a mature monocyte-derived IL-4-generated dendritic cell (DC). These observations could be useful in the development of a human vaccine against coccidiodomycosis.