An important feature of type 2 diabetes is a decrease in <i>β</i> -cell mass. Therefore, it is essential to find new approaches to stimulate <i>β</i> -cell proliferation. We have previously shown that heterozygous inactivation of the Na ⁺ /Ca ²⁺ exchanger (isoform 1; NCX1), a protein responsible for Ca ²⁺ extrusion from cells, increases <i>β</i> -cell proliferation, mass, and function in mice. Here, we show that <i>Ncx</i> 1 inactivation also increases <i>β</i> -cell proliferation in 2-year-old mice and that NCX1 inhibition in adult mice by four small molecules of the benzoxyphenyl family stimulates <i>β</i> -cell proliferation both <i>in vitro</i> and <i>in vivo</i> . NCX1 inhibition by small interfering RNA or small molecules activates the calcineurin/nuclear factor of activated T cells (NFAT) pathway and inhibits apoptosis induced by the immunosuppressors cyclosporine A (CsA) and tacrolimus in insulin-producing cell. Moreover, NCX1 inhibition increases the expression of <i>β</i> -cell-specific genes, such as <i>Ins1, Ins2,</i> and <i>Pdx</i> 1, and inactivates/downregulates the tumor suppressors retinoblastoma protein (pRb) and miR-193a and the cell cycle inhibitor p53. Our data show that Na ⁺ /Ca ²⁺ exchange is a druggable target to stimulate <i>β</i> -cell function and proliferation. Specific <i>β</i> -cell inhibition of Na ⁺ /Ca ²⁺ exchange by phenoxybenzamyl derivatives may represent an innovative approach to promote <i>β</i> -cell regeneration in diabetes and improve the efficiency of pancreatic islet transplantation for the treatment of the disease.