Abstract Aberrations of the TP53 pathway, whether by deletion or mutation, are increasingly recognized as one of the most important biological risk factors in chronic lymphocytic leukemia. Yet, there is little consensus on how to assess for TP53 defects in the clinic, and very few clinical studies to guide optimal management of such patients. In this review, we discuss the state-of-the-art in the assessment of the TP53 pathway, and review the evidence-base for therapeutic recommendations.