Simple SummaryTranscription Factor A Mitochondrial (TFAM) was first purified 35 years ago as an activator of mitochondrial transcription. Because of its critical contributions to mitochondrial DNA transcription and replication, this protein was viewed as a master regulator of mitochondrial biogenesis. However, now it is clear that TFAM’s cellular role is more nuanced than previously thought. In this review, we attempted to compile and assess various, at times contradictory, lines of evidence supporting this protein’s diverse roles. It is carried out in the belief that the resolution of the existing contradictions is a prerequisite for further advancements in the field.AbstractTranscription Factor A Mitochondrial (TFAM), through its contributions to mtDNA maintenance and expression, is essential for cellular bioenergetics and, therefore, for the very survival of cells. Thirty-five years of research on TFAM structure and function generated a considerable body of experimental evidence, some of which remains to be fully reconciled. Recent advancements allowed an unprecedented glimpse into the structure of TFAM complexed with promoter DNA and TFAM within the open promoter complexes. These novel insights, however, raise new questions about the function of this remarkable protein. In our review, we compile the available literature on TFAM structure and function and provide some critical analysis of the available data.