Chemotaxis, the directional cell migration guided by chemoattractant gradients, plays essential roles in many physiological processes, such as recruitment of neutrophils to sites of inflammation. Neutrophils detect chemoattractants by G protein-coupled receptors (GPCRs). Chemoattractant stimuli activate multiple signaling pathways to regulate directional migration of neutrophils. Recently, we identified a novel GPCR-mediated PLCβγ/ PKCβ/PKD1 signaling axis that regulates cofilin activity through cofilin phosphatase slingshot 2 (SSH2) and remodels actin cytoskeleton during neutrophil chemotaxis. In the future, it will be important to understand how multiple signaling pathways are spatiotemporally regulated to precisely control the rapid remodeling of actin cytoskeleton in the leading front of chemotaxing neutrophils.