Recent reports have shown that cannabinoid 1 receptors (CB1Rs) are expressed in pancreatic β cells, where they induce cell death by directly inhibiting activation of insulin receptor. Here I report that anti-apoptotic protein Bcl-2 and cell cycle regulator Cyclin D2 are involved in cannabinoid-induced β-cell death and growth arrest. Treatment of MIN6 and βTC6 cells with a synthetic CB1R agonist WIN55,212-2 leads to decrease in the expression of Bcl-2 and Cyclin D2, in turn inducing an arrest of the cell cycle in the G0/G1 phase and caspase-3-dependent apoptosis. Consistently, genetic deletion and pharmacological blockade of CB1Rs leads to increased β-cell survival and proliferation after injury due to increased levels of Bcl-2 and Cyclin D2. These findings provide evidence for involvement of Bcl-2 and Cyclin D2 in the regulation of β-cell survival and growth and will serve as a basis for developing new therapeutic interventions to enhance β-cell function and growth in diabetes.