The evolutionary conserved Notch pathway that first developed in metazoans and that was first discovered in fruit flies (Drosophila melanogaster) governs fundamental cell fate decisions and many other cellular key processes not only in embryonic development but also during initiation, promotion, and progression of cancer. On a first look, the Notch pathway appears remarkably simple, with its key feature representing a direct connection between an extracellular signal and transcriptional output without the need of a long chain of protein intermediaries as known from many other signaling pathways. However, on a second, closer look, this obvious simplicity exerts surprising complexity. There is no doubt that the enormous scientific progress in unraveling the functional mechanisms that underlie this complexity has recently greatly increased our knowledge about the role of Notch signaling for pathogenesis and progression of many types of cancer. Moreover, these new scientific findings have shown promise in opening new avenues for cancer prevention and therapy, although this goal is still challenging. Vol. III of the second edition of the book Notch Signaling in Embryology and Cancer, entitled Notch Signaling in Cancer, summarizes important recent developments in this fast-moving and fascinating field. Here, we give an introduction to this book and a short summary of the individual chapters that are written by leading scientists, covering the latest developments in this intriguing research area.