The ability to reprogram cell lineage specification through the activity of master regulatory transcription factors has transformed disease modeling, drug screening, and cell therapy for regenerative medicine. Recent advances in the engineering of synthetic transcription factors to modulate endogenous gene expression networks and chromatin states have generated a new set of tools with unique advantages to study and enhance cell reprogramming methods. Several studies have applied synthetic transcription factors in various cell reprogramming paradigms in human and murine cells. Moreover, the adaption of CRISPR-based transcription factors for high-throughput screening will enable the systematic identification of optimal factors and gene network perturbations to improve current reprogramming protocols and enable conversion to more diverse, highly specified, and mature cell types. The rapid development of next-generation technologies with more robust and versatile functionality will continue to expand the application of synthetic transcription factors for cell reprogramming.