The transcriptional machinery is essential for gene expression and regulation; dysregulation of transcription can result in a range of pathologies, including neurodegeneration, cancer, developmental disorders and cardiovascular disease. A key component of RNA polymerase II-mediated transcription is the basal transcription factor IID, which is formed of the TATA box-binding protein (TBP) and 14 TBP-associated factors (TAFs), the largest of which is the TAF1 protein, encoded on the X chromosome (Xq13.1). TAF1 is dysregulated in X-linked dystonia–parkinsonism and congenital mutations in the gene are causative for neurodevelopmental phenotypes; TAF1 dysfunction is also associated with cardiac anomalies and cancer. However, how TAF1 contributes to pathology is unclear. Here, we highlight the key aspects of the TAF1 gene and protein function that may link transcriptional regulation with disorders of development, growth and adult-onset disorders of motor impairment. We highlight the need to experimentally investigate the full range of TAF1 messenger RNA variants and protein isoforms in human and mouse to aid our understanding of TAF1 biology. Furthermore, the X-linked nature of TAF1 -related diseases adds complexity to understanding phenotypes. Overall, we shed light on the aspects of TAF1 biology that may contribute to disease and areas that could be addressed for future research and targeted therapeutics.