The importance of studying p53 pathway defects in chronic lymphocytic leukemia (CLL) has been promoted by the demonstration of the fundamentally different clinical course of patients with 17p deletion. The observation of resistance to chemotherapy and mutation of the remaining TP53 allele explain the clinical presentation of CLL with 17p deletion. Here we review recent evidence that cases with TP53 mutation in the absence of the deletion of 17p have a similar clinical and biological course as cases carrying the deletion 17p. In addition, other principal components of the DNA damage pathway reportedly are de-regulated by mutation (ATM), deletion (ATM) or potentially more complex down-regulation (miR-34a) in CLL. Nonetheless, challenges remain because we can only explain resistance in a proportion of the cases that are resistant to first line treatment. This is of particular practical interest because our armamentarium of drugs in clinical use that acts independent of the DNA damage pathway is growing, for example antibody-based treatment (alemtuzumab), immuno-modulating drugs (lenalidomide), CDK inhibitors (flavopiridol) and steroids.