The principal social activity of Myxococcus xanthus is to organize a dynamic multicellular structure, known as a swarm. Although its cell density is high, the swarm can grow and expand rapidly. Within the swarm, the individual rod-shaped cells are constantly moving, transiently interacting with one another, and independently reversing their gliding direction. Periodic reversal is, in fact, essential for creating a swarm, and the reversal frequency controls the rate of swarm expansion. Chemotaxis toward nutrient has been thought to drive swarming, but here the nature of swarm growth and the impact of genetic deletions of members of the Frz family of proteins suggest otherwise. We find that three cytoplasmic Frz proteins, FrzCD, FrzF, and FrzE, constitute a cyclic pathway that sets the reversal frequency. Within each cell these three proteins appear to be connected in a negative-feedback loop that produces oscillations whose frequencies are finely tuned by methylation and by phosphorylation. This oscillator, in turn, drives MglAB, a small G-protein switch, to oscillate between its GTP-and GDP-bound states that ultimately determine when the cell moves forward or backward. The periodic reversal of interacting rod-shaped cells promotes their alignment. Swarm organization ensures that each cell can move without blocking the movement of others.For many years myxobacterial swarming has been viewed as a chemotactic process in which swarm cells are attracted to greener pastures beyond the swarm edge (9,25,34,40). Also, Myxococcus xanthus is said to be attracted to prey bacteria when it forms concentric ripples that advance toward the prey (1), but how ripples imply chemotaxis has not been explained. Investigating chemotaxis in M. xanthus, a Gram-negative deltaproteobacterium, has been motivated by the presence of six frizzy genes, five of which encode proteins with some similarity (28 to 40% identity at the amino acid level) to the core chemotaxis proteins found in Escherichia coli and Salmonella (2). Despite continuing attempts to identify chemotactic attractants, only phosphatidylethanolamine (PE), a normal constituent of M. xanthus membranes, has been found to increase the frequency of reversals of starved cells, a process called stimulation (18). Stimulation, however, does not depend on the frizzy proteins (23, 39). Since no methyl-accepting chemotaxis (MCP) protein receptor for PE has been identified, extracellular PE might instead be interacting with the cell's outer membrane and the largely unknown machinery that induces reversal of gliding direction. A serious molecular difficulty with the chemotactic view of M. xanthus behavior is that FrzCD, unlike the methyl-accepting chemotaxis proteins of E. coli, lacks both a transmembrane and an extracellular domain at its N terminus that would respond to attractant or repellant binding to a receptor. FrzCD is, moreover, localized to the cytoplasm (5, 24). The FrzE histidine kinase, like its E. coli homolog CheA, has no sensory domain and is also a cytoplasmic protein. FrzE...