The epigenome is now widely studied in order to gain insights into normal cellular events and to understand how dysregulatory processes are involved in disease phenotypes. As data emerge from these studies, the question is now arising whether the epigenetic regulators being studied are capable of autonomous decisions or whether they instead in part or mostly reflect the activities of transcription factors. A re-interpretation of epigenomic data with a transcription factor-centric perspective suggests that our insights into cellular processes reflected by the epigenome are enhanced by this alternative model. We can also use the transcription factor viewpoint to re-interpret the original idea of an “epigenetic landscape” to create a neo-Waddingtonian model of cellular events causing human disease risk. These new ways of thinking about epigenetic regulation should be valuable in guiding the study and interpretation of the epigenome in human disease.