Inhibitors of the MDM2-p53 interaction are actively being developed as anti-cancer agents. Drug-induced interference with the MDM2 E3 ligase function or with MDM2 protein-protein interactions abrogates tonic suppression and destruction of the p53 protein; consequently, p53 steady state levels rise resulting in the induction of p53-dependent anti-proliferative and pro-apoptotic genes. Some cancerous cells harboring wild type p53 respond to MDM2 inhibitor-induced elevated p53 protein levels with apoptotic cell death while non-malignant cells, for poorly understood reasons, appear relatively resistant. Deciphering the mechanisms of resistance or susceptibility to MDM2 inhibitor-induced cancer cell death is of significant importance for the clinical development and applications of MDM2 inhibitory compounds and serves to illuminate aspects of MDM2 and p53 biology. Using data from ex vivo MDM2 inhibitor treatment of a large cohort of molecularly highly characterized CLL cases, we were able to demonstrate the central role of p53 status as a determinant of resistance in this common leukemia. In the context of these experimental findings, we summarize pertinent knowledge of the biology of p53, MDM2, p53 target genes and MDM2 binding proteins. Finally, using data from a large SNP-array-based high-density genomic profiling study in CLL, we summarize the genomic copy number and allele status for important p53 effector genes as well as for MDM2 binding/target proteins, thus demonstrating the power of high resolution genomic analysis in support of targeted drug development.