Specifically, we review the predictive impact, if any, of TP53 aberrations, deletion of the long arm of chromosome 11, complex karyotype or genomic complexity, unmutated IGHV, B cell receptor stereotypy, mutated NOTCH1 and mutated BIRC3. Furthermore, we discuss future perspectives for CLL with high-risk molecular features, focusing on upcoming agents in the therapeutic armamentarium of CLL. This evidence concerns the gene BIRC3 and B-cell chronic lymphocytic leukemia.