Tribbles homolog 2 (Trib2) is a pseudo serine/threonine kinase that functions as a scaffold or adaptor in many signaling pathways. Trib2 can interact with E3 ubiquitin ligases and affect the protein stability of downstream effectors, controlling transcription, cell proliferation, apoptosis, survival, and differentiation, with effects on metabolism and disease. In contrast to its critical role in cell development and homeostasis, Trib2 is also induced by mitogens and enhances cancer cell proliferation. Its involvement in several hematopoietic cancers and solid tumors makes it a valuable biomarker for cancer diagnosis and treatment. Recent studies have shown that Trib2 also plays a major role in determining the fate of stem cells, which have the potential to self-renew and differentiate into many different cell types. Trib2 may be necessary for colony formation and self-renewal of embryonic stem cells (ESCs), and loss of Trib2 function is associated with ESC differentiation. And consistent with its regulation of pluripotency, Trib2 also plays an important role in the reprogramming of somatic cells. Future studies should focus on the mechanisms underlying the critical role of this protein in cancer and stem cell fate decisions, helping to guide the development of novel targeted therapeutics for chemoresistant cancers.