Neutrophils navigate interstitial gradients in vivo through a search and run strategy. Model for neutrophil gradient sensing in vivo. Before encountering the gradient, neutrophils have a pre-established, unspecific polarity, and movement. Upon gradient exposure, neutrophils have a low chance of resolving gradient direction without active actin dynamics, therefore a search phase is required. During this phase, front actin network expansion via Arp2/3 promotes exploration and gradient sampling (illustrated by green spots), culminating in small turns towards the gradient source. Subsequently, cells switch to a running phase, whereby fast actin flows and Myosin-II contractility enforce fast and persistent motion towards the gradient.