TP53 disruption in Chronic Lymphocytic Leukaemia ha long been known to hold vital prognostic information as well as dictate the appropriate course of treatment to be followed for patients. TP53 status is commonly assessed by FISH for del(17p) and Sanger sequencing for TP53 mutational analysis. At present, current screening methods for these mutations could miss diagnostically relevant mutations potentially leading to inappropriate treatment decisions. In addition low levels of mutations that are proving to be clinically relevant may not be detected with current techniques. This review looks at the structure, function and regulation of the TP53 protein, the mutations found in cancer and CLL, the relevance of TP53 disruption in CLL and the current screening methods for TP53 mutations including Next-generation sequencing.