p53 gene mutations are rarely detected at diagnosis in common hematologic cancers such as multiple myeloma (MM), acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL), and Hodgkin’s disease (HD), although their prevalence may increase with progression to more aggressive or advanced stages. Therapeutic induction of p53 might therefore be particularly suitable for the treatment of hematologic malignancies. Some of the anti-tumour activity of current chemotherapeutics has been derived from activation of p53. However, until recently it was unknown if p53 signaling is functional in some of the hematologic cancers including multiple myeloma (MM) and if p53 activity is sufficient to trigger an apoptotic response. With the recent discovery of nutlins, which represent the first highly selective small molecule inhibitors of the p53-MDM2 interaction, pharmacologic tools are now available to induce p53 irrespective of upstream signaling defects, and to functionally analyze the downstream p53 pathway in primary leukaemia and lymphoma cells. Combination therapy is emerging as a key factor, and development of non-genotoxic combinations seems very promising for tackling the problems of toxicity and resistance. This review will highlight recent findings in the research into molecules capable of modulating p53 protein activities and mechanisms that activate the p53 pathway restoring response to therapy in hematological malignancies.