In the last 5 years, treatment approaches for CLL patients have been revolutionized by the introduction of novel agents such as anti-BTK ibrutinib and anti-BCL2 venetoclax, that have shown an unprecedented efficacy in CLL with TP53 deletion/mutation and in R/R cases and that more recently have also moved to the first line setting, with some differences in the indications according to the country. The gene discussed is TP53; the disease is B-cell chronic lymphocytic leukemia.