The gene encodes the tumor suppressor protein p53, which plays a critical role in genomic stability and cell cycle regulation. mutations are prevalent in approximately half of all human malignancies and are associated with poor clinical outcomes, including increased genomic instability, chemoresistance, and reduced survival rates. However, the prognostic and predictive value of status remains inconsistent across cancer types. Chronic lymphocytic leukemia (CLL) stands out as a disease where alterations have a well-established clinical significance, influencing treatment decisions and patient prognosis. In CLL, mutations and 17p deletions are strongly correlated with advanced disease stages, resistance to chemo-immunotherapy, and poor overall survival. The European Research Initiative for CLL (ERIC) has recognized status as a crucial prognostic biomarker, advocating for its routine assessment in clinical practice. Given the limitations of traditional therapies in -mutated CLL, novel targeted therapies, including BCL2 and BTK inhibitors, as well as CAR-T cell therapy, are being explored to improve patient outcomes. This review provides an in-depth analysis of the evolving role of status in CLL, with a particular focus on emerging therapeutic strategies, including CAR-T cell therapy, and their potential to overcome -driven treatment resistance.