Low dose radiotherapy is an effective palliative treatment for follicular lymphoma, inducing the rapid apoptosis of the neoplastic B cells. Comparison of the gene expression profiles of follicular lymphoma biopsy samples taken before and after radiation shows that the intact p53 pathway is the driving force to the apoptotic process. Death of the Bcl-2 overexpressing B cells can be explained by the prominent induction of the extrinsic apoptotic pathway, with an active role of the neoplastic microenvironment for the expression of death receptor ligands and the clearance of the apoptotic cells. These insights have implications for the design of new protocols in the treatment of follicular lymphoma.