During the immune response, immature dendritic cells (DCs) undergo a maturation process that involves extensive changes in cell adhesion and motility, culminating in the migration of the mature cells to lymph tissue. The dissolution of podosomes – actin-rich adhesive structures that actively degrade the extracellular matrix – is a hallmark of DC maturation, but the signalling pathways that control this process remain uncharacterised. On page 1096, Frank van Leeuwen and colleagues investigate the role of prostaglandin E2 (PGE2) in podosome disassembly. The authors previously showed that PGE2 stimulated the loss of podosomes in DCs; here, they show that it does this by acting via the PGE2 receptors EP2 and EP4. In addition, myosin IIA localises to podosomes and is necessary for their disassembly in response to PGE2. In HL-60 cells induced to form podosomes, the authors show, PGE2 treatment activates the GTPase RhoA, and in DCs, the blockade of Rho-kinase activity with chemical inhibitors causes podosomes to persist. Based on these results, the authors propose that PGE2 mediates podosome dissolution by myosin-II-mediated contractility downstream of RhoA and Rho-kinase activation. These data provide new insight into the remodelling of the cytoskeleton during DC maturation.