The lipofuscin fluorophore A2E has been shown to mediate blue light-induced damage to retinal pigmented epithelial (RPE) cells. To understand the events that lead to RPE cell apoptosis under these conditions, we explored signaling pathways upstream of the cell death program. Human RPE cells (ARPE-19) that had accumulated A2E were exposed to blue light to induce apoptosis and the involvement of the transcription factors p53 and c-Abl and the mitogen activated protein kinases p38 and JNK were examined. We found that A2E/blue light caused upregulation and phosphorylation of c-Abl, and upregulation of p53. Pretreatment with the c-Abl inhibitor STI571 and transfection with siRNA specific to c-Abl and p53 prior to irradiation reduced A2E/blue light-induced cell death. Gene and protein expression of JNK and p38 was upregulated in response to A2E/blue light. Treatment with the JNK inhibitor SP600125 before irradiation resulted in increase in cell death whereas inhibition of p38 with SB203580 had no effect. This study indicates that c-Abl and p53 are important for execution of the cell death program initiated in A2E-laden RPE cells exposed to blue light, while JNK might play an anti-apoptotic role.