We will outline studies that advanced our understanding of the mechanisms controlling the activities of GRKs and their effects on neutrophil guidance in health and disease, with a focus on CXCR4 functions, in light of WHIM-associated neutropenia and the deregulation of GRK expression in pathological conditions and their interplay with non-GPCRs. The gene discussed is CXCR4; the disease is Decreased total neutrophil count.