Therapeutic modalities including surgery, radiation, chemotherapy and targeted therapies have had an impact on standard of care for cancer patients; however, they do not change the mortality statistics. Also, de novo and acquired resistance are major issues with all known targeted therapies. In addition, induction of tumor immunity and memory is critical for durable remission following conventional or pathway-directed cancer therapies. Immune responses also shape cancer heterogeneity, a hallmark feature aiding clonal survival, therapy resistance and dissemination of cancer. Moreover, inter-individual differences due to racial/ethnic backgrounds may alter host immunity responsible for the cancer immunosurveillance and elimination, leading to immune suppression and cancer escape. One basis of disparity in tumor incidence, progression, or therapeutic outcomes could lie in the components of Notch intercellular communication system which provide instructive signals for a variety of pathways regulating cell commitment and differentiation including context-dependent lymphocyte polarization in tumor microenvironment. Notably, Notch signaling in hematopoietic cells is perturbed by tumor growth for its advantage, and there are indications that differences in Notch components could underlie poor cancer prognosis in certain populations. Here, we discuss the oncogenic and immunogenic aspects of Notch which can inform on cancer health disparities and therapeutic outcomes.