N-formyl peptides, such as fMet-Leu-Phe (fMLP), are some of the first identified and most potent chemoattractants for phagocytic leukocytes. In addition to the bacterial peptide fMLP and the putative endogenously produced formylated peptides, we recently identified a number of other novel peptide agonists that selectively activate the prototype formyl peptide receptor (FPR) and/or its variant FPRL1. These agonists include several synthetic peptide domains derived from the envelope proteins of the human immunodeficiency virus type 1 (HIV-1) and intact human acute phase serum protein serum amyloid A. The activation of FPR and/or FPRL1 in monocytes by these agonists resulted in increased cell migration, calcium mobilisation and the heterologous down-regulation of the expression and function of chemokine receptors, notably CCR5 and CXCR4, two crucial fusion co-receptors for HIV-1. This down-regulation of CCR5 by FPR and FPRL1 agonists was associated with a rapid serine phosphorylation of CCR5. The desensitisation of CCR5 by FPR or FPRL1 agonists, not only inhibited its biological function induced by chemokine ligands, but also interfered with its capacity to act as a fusion co-receptor for monocyte tropic HIV-1. Thus, heterologous desensitisation by FPR and FPRL1 may play an important role in orchestrating the host innate immune responses which generate multiple chemotactic stimulants. Furthermore, the understanding of the structural and biochemical basis of FPR/FPRL1 activation may lead to the development of novel immunoregulatory and anti-HIV agents that emulate the process of heterologous desensitisation.