Cyclic-3′,5′-adenosine monophosphate (cAMP) is an ancient second messenger but organizing signaling selectivity on the nanoscale is poorly understood. Examining transport of a new fluorescent cAMP probe, Bock and coworkers observe “buffered diffusion” and establish phosphodiesterase activity can organize cAMP nanodomains, while Zhang and coworkers find that protein kinase A regulatory subunits assemble liquid droplets to further localize cAMP signaling.