Leukocytes accumulate at sites of inflammation and microbial infection in direct response to locally produced chemotactic factors, which signal through specific G protein-coupled receptors. The first chemotactic factors to be structurally defined were the N-formyl peptides. Unlike other leukocyte chemoattractants, N-formyl peptides could originate from either an endogenous source, such as the mitochondrial proteins of ruptured host cells, or an exogenous source, such as the proteins of invading pathogens. This suggests that the formyl-peptide receptor (FPR) and its variant FPRL1 (FPR-like 1) are involved in host defense against bacterial infection and in the clearance of damaged cells. Recently, additional, more complex, roles for these receptors have been proposed because FPR, and to a greater extent FPRL1, have been found to interact with a menagerie of structurally diverse pro- and anti-inflammatory ligands associated with different diseases, including amyloidosis, Alzheimer's disease, prion disease and HIV. How these receptors recognize such diverse ligands, which are the most important in vivo, and how they contribute to disease pathogenesis and host defense are basic questions currently under investigation that could lead to new therapeutic targets.