NOTCH1 and B-cell chronic lymphocytic leukemia: First, we will present the details of structure and mechanisms of the NOTCH1 pathway, with particular attention to the multiple steps that are required for receptor activation and processing; then we will focus on CLL, to dissect the anatomy of NOTCH1 mutations and their impact on the regulation and stability of NOTCH1 active protein and the main functional consequences on CLL pathobiology; finally, we will dive deeper in the other physiological and pathological mechanisms that drive Notch activation in CLL, beyond the presence of NOTCH1 somatic mutations.