The regulation of mammary gland development depends on a variety of signaling pathways, that are concerned with cell differentiation decisions and cell fate. The Neurogenic Locus Notch Homolog 4 (Notch4) pathway masters and preserves a balance among cellular multiplication, differentiation and cell death through its crucial role in stem cells regulation. Notch4 receptor is a member of the Notch family which is expressed in mammary epithelium and endothelial cells of vessels. Abnormal expression of Notch4 receptor has been detected in different types of neoplastic and preneoplastic lesions, suggesting that Notch4 may act as a proto-oncogene. Overexpression or genetic mutations of Notch4 receptor and its ligands may induce breast cancer by activating target genes, cross-talking with other pathways and giving the spark for stem cell deregulation, causing tumor initiation, maintenance, progression, treatment resistance and relapse. Notch4 Overexpression in breast cancer has been documented as a prognostic marker, and is related to the development of aggressive clinico-pathological and biological phenotypes of breast cancer.