In the developing vertebrate embryo, segmentation initiates through the formation of repeated segments, or somites, on either side of the posterior neural tube along the anterior to posterior axis. The periodicity of somitogenesis is regulated by a molecular oscillator, the segmentation clock, driving cyclic gene expression in the unsegmented paraxial mesoderm, from which somites derive. Three signaling pathways underlie the molecular mechanism of the oscillator: Wnt, FGF, and Notch. In particular, Notch has been demonstrated to be an essential piece in the intricate somitogenesis regulation puzzle. Notch is required to synchronize oscillations between neighboring cells, and is moreover necessary for somite formation and clock gene oscillations. Following ligand activation, the Notch receptor is cleaved to liberate the active intracellular domain (NICD) and during somitogenesis NICD itself is produced and degraded in a cyclical manner, requiring tightly regulated, and coordinated turnover. It was recently shown that the pace of the segmentation clock is exquisitely sensitive to levels/stability of NICD. In this review, we focus on what is known about the mechanisms regulating NICD turnover, crucial to the activity of the pathway in all developmental contexts. To date, the regulation of NICD stability has been attributed to phosphorylation of the PEST domain which serves to recruit the SCF/Sel10/FBXW7 E3 ubiquitin ligase complex involved in NICD turnover. We will describe the pathophysiological relevance of NICD-FBXW7 interaction, whose defects have been linked to leukemia and a variety of solid cancers.