The establishment of left-right organ asymmetry in vertebrates requires leftward flow generated by motile cilia at the embryonic node, but the precise mechanism by which flow triggers asymmetric signaling pathways has remained unclear. Petra Pennekamp, Hiroshi Hamada and colleagues (Science, published online 13 September 2012; doi:10.1126/science.1222538) now provide strong experimental evidence that mechanosensory cilia located in the perinodal region have a key role in establishing the vertebrate left-right axis. Using a series of elegant transgenic models coupled with an experimental system for generating artificial flow across the node region, they show that Pkd2, which has previously been implicated in cilia-dependent mechanosensation in kidney cells, is specifically required in crown cells located at the periphery of the node to sense directional flow and initiate downstream signaling events. They further show that the ability of crown cells to respond to flow is dependent on ciliary localization of Pkd2. Additional work suggests that this Pkd2-dependent flow sensing results in elevated calcium signaling in crown cells on the left side of the node, which initiates the asymmetric patterns of gene expression responsible for specifying organ asymmetries.