Cancer therapy has witnessed major advances in the last few decades. However, the conventional therapies have a narrow therapeutic application, and the responses produced are generally unpredictable and are often non-curative. New strategies to combat cancer are being developed, one of the most promising of which is the use of non-genotoxic chemicals that are able to rescue the tumor suppressor function of p53 in cancer cells. In this review, we first discuss: (i) the current knowledge on the role of p53 in determining the fate of human normal and malignant cells following exposure to cancer therapeutic agents; and (ii) the biological consequences of the failure of cancer cells to implement p53-mediated responses in terms of development of highly metastatic “karyoplasts” which exhibit both selfrenewal and treatment-resistant properties. We next provide an update on the potential anticancer properties of diverse types of pharmacological modulators of p53, including histone deacetylase inhibitors (e.g., trichostatin A), aromatase inhibitors (e.g., Anastrozole), and the nuclear export inhibitor leptomycin B. In addition, we highlight the various shortcomings of in vitro assays that are universally used for preclinical evaluation of anti-neoplastic properties of new drugs, and describe alternative cytotoxicity assays that circumvent some of these shortcomings.