The specification of cell fate is critical for proper cell differentiation and organogenesis. In endocrine tissues, this process leads to the differentiation, often a multistep process, of hormone-producing cells. This process is driven by a combination of transcription factors (TFs) that includes general factor, tissue-restricted, and/or cell-restricted factors. The last 2 decades have seen the discovery of many TFs of restricted expression and function in endocrine tissues. These factors are typically critical for expression of hormone-coding genes as well as for differentiation and proper function of hormone-producing cells. Further, genes encoding these tissue-restricted TFs are themselves subject to mutations that cause hormone deficiencies. Although the model that emerged from these 2 decades is one in which a specific combination of TFs drives a unique cell specification and genetic program, recent findings have led to the discovery of TFs that have the unique property of being able to remodel chromatin and thus modify the epigenome. Most importantly, such factors, known as pioneer TFs, appear to play critical roles in programming the epigenome during the successive steps involved in cell specification. This review summarizes our current understanding of the mechanisms for pioneer TF remodeling of chromatin. Currently, very few TFs that have proven pioneer activity are known, but it will be critical to identify these factors and understand their mechanisms of action if we are to harness the potential of regenerative therapies in endocrinology.