Transcription factors control, coordinate, and separate the functions of distinct network modules spatially and temporally. In this review, we focus on the transcription factor 21 (TCF21) network, a highly conserved basic-helix-loop-helix (bHLH) protein that functions to integrate signals and modulate gene expression. We summarize the molecular and biological properties of TCF21 control with an emphasis on molecular and functional TCF21 interactions. We suggest that these interactions serve to modulate the development of different organs at the transcriptional level to maintain growth homeostasis and to influence cell fate. Importantly, TCF21 expression is epigenetically inactivated in different types of human cancers. The epigenetic modification or activation and/or loss of TCF21 expression results in an imbalance in TCF21 signaling, which may lead to tumor initiation and, most likely, to progression and tumor metastasis. This review focuses on research on the roles of TCF21 in development and tumorigenesis systematically considering the physiological and pathological function of TCF21. In addition, we focus on the main molecular bases of its different roles whose importance should be clarified in future research. For this review, PubMed databases and keywords such as TCF21, POD-1, capsulin, tumors, carcinomas, tumorigenesis, development, and mechanism of action were utilized. Articles were selected within a historical context as were a number of citations from journals with relevant impact.