The allograft inflammatory factor-1 (AIF-1) is a 17 kDa interferon-gamma (IFN-gamma) inducible Ca(2+)-binding EF-hand protein that is encoded within the HLA class III genomic region. Three proteins including ionized Ca(2+)-binding adaptor 1, microglia response factor-1, and daintain are identical with AIF-1. The expression of AIF-1 was mostly limited to the monocyte/macrophage lineage, and augmented by cytokines such as IFN-gamma. It was assumed that AIF-1 was a novel molecule involved in inflammatory responses, allograft rejection, as well as the activation and function of macrophages. However, it has been reported that AIF-1 is also expressed in macrophages and microglial cells in autoimmune diseases such as experimental autoimmune encephalomyelitis, neuritis and uveitis models, suggesting that AIF-1 may play a pivotal role in autoimmunity. In the present manuscript, the genomic and functional characteristics of AIF-1 family proteins as well as their immune regulatory effects are reviewed.