A novel class of extracellular signaling peptides has been identified in Gram-positive bacteria that are actively transported into the cell to interact with intracellular receptors. The defining members of this novel class of signaling peptides are the Phr peptides of Bacillus subtilis and the mating pheromones of Enterococcus faecalis. These peptides are small and unmodified, gene encoded, and secreted by the bacterium. Most of these peptides diffuse into the extracellular medium, and when their concentration is sufficiently high, they are then actively transported into the cell by an oligopeptide permease (Opp). Once inside the cell, these peptides interact with an array of intracellular receptors. In B. subtilis, the Phr peptides regulate development of environmentally resistant spores and genetically competent cells (i.e. the natural ability to take up exogenous DNA). In E. faecalis, the mating pheromones regulate cell-cell transfer of plasmids, many of which encode antibiotic resistance or virulence factors. At least one component of the signaling pathway for these peptides is conserved in many bacteria, Opp. Opp is a non-specific transporter that transports peptides for use as carbon and nitrogen sources. The possibility that other bacteria could possess similar intracellularly functioning signaling peptides is discussed.