In the last decade, a new wave of inspired research surrounding a transcription factor’s role in blood-sugar homeostasis has emerged. Transcription Factor 7-like 2 (TCF7L2 or TCF4), a member of the Wnt signaling pathway, is intimately involved in suppressing glucagon synthesis. It also may affect β-cell function. Regiospecific trends concerning the selection of its molecular variants, their dependency on environmental and behavioral changes, and their relative associations with type 2 diabetes (T2D) have become well documented. This dynamic and nuanced understanding of one T2D risk factor should be desired in all other phases of study. An open and incorporative mindset such as this can revitalize the research field.