Ligand engaged chemoattractant receptors trigger Gα i subunit nucleotide exchange stimulating the activation of downstream effector molecules. Activated chemoattractant receptors also dock G-protein-coupled receptor kinases (GRKs) that help mediate receptor desensitization. Here, we show that the B cell-specific loss of GRK2 severely disrupts B cell trafficking and immune cell homeostasis. The GRK2 deficiency in developing murine B cells leads to a severe immune phenotype including a major reduction of bone marrow IgD+ cells; splenomegaly with a loss of white pulp and grossly expanded red pulp; a deficit of Peyer’s patches; and small lymph nodes with marked reductions in B cell numbers. The major phenotypes in these mice arise from excessive S1PR1 signaling combined with inadequate homeostatic chemokine receptor signaling. CXCL13 signaling is the most severely compromised. Our data also indicates that in B cells S1PR1 signals constitutively as blocking S1PR1 signaling with an S1PR1 antagonist enhanced CXCL13 triggered wild type B cell migration. Furthermore, blocking S1PR1 signaling in the GRK2 deficient B cells partially corrected their poor response to chemokines. Treating mice lacking GRK2 expression in their B cells with an S1PR1 antagonist partially normalized B trafficking into lymph node and splenic follicles. These findings reveal the critical interdependence of Gα i linked signaling pathways in controlling B lymphocyte trafficking.