Wild-type neutrophils in the bone marrow express CXCR4 and interact with stromal cells expressing SDF1. This interaction activates CXCR4 (“on”), sending a blocking signal to the cells' motility apparatus, which prevents egress from the marrow. As the neutrophils mature, CXCR4-SDF1 is internalized and degraded (“off”), which leads to Rac activation, allowing the cells to migrate out of the marrow. WHIM syndrome patients express a dominant gain-of-function C-terminal truncation of CXCR4. Walters and colleagues have shown that CXCR4^WHIM nonetheless requires the binding of SDF-1 to activate CXCR4^WHIM (“on”), blocking motility. CXCR4^WHIM is not internalized, so the “on” signal persists, resulting in retention of neutrophils in the marrow, and ultimately apoptosis. This retention can be bypassed, either by knocking down SDF-1, or activating Rac, the G-protein that drives actin polymerization and neutrophil motility.