The Notch signaling pathway is an evolutionarily conserved cell signaling system present in most multicellular organisms, as it controls cell fate specification by regulating cell proliferation, differentiation, apoptosis, and survival. Regulation of the Notch signaling pathway can be achieved at multiple levels. Notch proteins are involved in lineage fate decisions in a variety of tissues in various species. Notch is essential for T lineage cell differentiation including T versus B and αβ versus γδ lineage specification. In this paper, we discuss Notch signaling in normal T-cell maturation and differentiation as well as in T-cell acute lymphoblastic lymphoma/leukemia.