Drs Hanano and Kaufmann[1]have recently written a thoughtful review of the current state of our knowledge regarding the classification and biology of Pneumocystis carinii, and the host immune response to this important opportunistic pathogen. Several important points were made regarding host defense to P. carinii that indicate the deficits in our current knowledge. Perhaps the most important is the mechanism of killing of the microorganisms. This has mainly resulted from the inability to propagate P. carinii in culture systems beyond a period of 1–2 weeks. As pointed out by Hanano and Kaufmann, alveolar macrophages may be the first line of defense against P. carinii pneumonia (PCP); however, they are clearly insufficient for clearance in the absence of recognition by specific CD4+ T cells. Although it has been shown that specific recognition by class II-restricted CD4+ cells is required for resolution of PCP, the specific role that these cells play in eliminating the microorganisms is unclear. This has been particularly difficult to determine because clearance of PCP can take place in the absence of several cytokines elaborated by CD4+ cells, including interferon γ, interleukin 4 (IL-4) and IL-5 (Ref. [1]; B.A. Garvy, unpublished[2]). These observations indicate that either these cytokines are irrelevant or that there are redundancies in the mechanism by which CD4+ cells stimulate the clearance of P. carinii. As the CD40–CD40-ligand interaction is necessary for resolution of PCP, it might be that direct stimulation of CD40-bearing cells by CD4+ cells is the pivotal event leading to clearance.