Numerous physiological and pathological stimuli promote the rearrangement of the actin cytoskeleton, thereby modulating cellular motile functions. Although it seems intuitively obvious that cell motility requires coordinated protein biosynthesis, until recently the linkage between cytoskeletal actin dynamics and correlated gene activities remained unknown. This knowledge gap was filled in part by the discovery that globular actin polymerization liberates myocardin-related transcription factor (MRTF) cofactors, thereby inducing the nuclear transcription factor serum response factor (SRF) to modulate the expression of genes encoding structural and regulatory effectors of actin dynamics. This insight stimulated research to better understand the actin-MRTF-SRF circuit and to identify alternative mechanisms that link cytoskeletal dynamics and genome activity.