Myocardial ischemic injury is characterized by an extensive loss of myocytes due to apoptosis/necrosis followed by an immune/inflammatory response and reestablishment of tissue integrity by a fibrotic scar. Prevention of rupture due to scar formation however, compromises contractility and reduces cardiac function. As bone marrow derived stem/precursor cells (BMSCs) have the ability to trans-differentiate and aid in the regeneration of injured myocardium, we studied BMSCs and their response to inflammation. BM cell mobilization, egress from the BM and recruitment to the site of injury can be regulated by signals through G protein-coupled receptors (GPCRs). β-arrestins are known for their GPCR signaling termination and scaffolding functions. Here, we explored the potential role for β-arrestins expressed in total BM in mediation of the initiation and progression of inflammation. We investigated the role β-arrestin1 (βArr1) and β-arrestin2 (βArr2) with respect to modulation of regenerative competence of BMSCs and inflammatory cells and their contribution to cardiac repair following ischemic injury. We carried out BM transplants to determine whether βArrs may be involved in cardiac repair. WT mice were irradiated and received BM transplants from WT, βArr1 or βArr2 KO donor mice. Subsequent to BM reconstitution, mice underwent MI and their recovery and progress were followed. Interestingly, βArr1 and βArr2 KO chimeras had inferior outcomes than mice receiving WT BM. This included significantly decreased post-MI survival with βArr2 KO BM and both βArr chimeras had significantly lower cardiac function post-MI compared to WT BM recipients. Histology shows that both chimeras had larger infarcts, accelerated rate of hypertrophy, quicker induction of fibrosis, exacerbated cell infiltration and increased number of apoptotic cells. At 3d post-MI immune cell intrusion of βArr2KO chimeric hearts was highest and the blood plasma content of TNFα and IL-6 was increased. We conclude that βArrs play a novel role downstream of GPCR desensitization in cardiac progenitor/inflammatory cells in the BM and are critical in the heart’s response to ischemic injury via cardiac repair and regeneration.