Simple SummaryTumor Suppressor Candidate 2 (TUSC2) is an important tumor suppressor that negatively regulates cancer growth and progression in multiple cancer types. TUSC2 was first discovered as a candidate tumor suppressor gene that is located on a frequently deleted region of chromosome 3p21.3 in lung cancer. Since its initial discovery in lung cancer, TUSC2 loss has also been reported in glioma, sarcoma, and cancers of the breast, ovaries, and thyroid. When TUSC2 is re-expressed in these cancer types, it reduces cancer cell growth and promotes cell death. In normal cells, TUSC2 regulates the immune system and prevents the development of autoimmune diseases. TUSC2 also regulates calcium movement within the cell and the mitochondria, which is important for overall cellular function. Lastly, TUSC2 loss promotes premature aging with the development of hearing loss and sporadic Alzheimer’s disease. Altogether, these findings define a vital role that TUSC2 plays in normal and cancerous cells.AbstractTumor Suppressor Candidate 2 (TUSC2) was first discovered as a potential tumor suppressor gene residing in the frequently deleted 3p21.3 chromosomal region. Since its discovery, TUSC2 has been found to play vital roles in normal immune function, and TUSC2 loss is associated with the development of autoimmune diseases as well as impaired responses within the innate immune system. TUSC2 also plays a vital role in regulating normal cellular mitochondrial calcium movement and homeostasis. Moreover, TUSC2 serves as an important factor in premature aging. In addition to TUSC2′s normal cellular functions, TUSC2 has been studied as a tumor suppressor gene that is frequently deleted or lost in a multitude of cancers, including glioma, sarcoma, and cancers of the lung, breast, ovaries, and thyroid. TUSC2 is frequently lost in cancer due to somatic deletion within the 3p21.3 region, transcriptional inactivation via TUSC2 promoter methylation, post-transcriptional regulation via microRNAs, and post-translational regulation via polyubiquitination and proteasomal degradation. Additionally, restoration of TUSC2 expression promotes tumor suppression, eventuating in decreased cell proliferation, stemness, and tumor growth, as well as increased apoptosis. Consequently, TUSC2 gene therapy has been tested in patients with non-small cell lung cancer. This review will focus on the current understanding of TUSC2 functions in both normal and cancerous tissues, mechanisms of TUSC2 loss, TUSC2 cancer therapeutics, open questions, and future directions.