The tooth–periodontium complex and its nerves have active reciprocal regulation during development and homeostasis. These effects are predominantly mediated by a range of molecules secreted from either the nervous system or the tooth–periodontium complex. Different strategies mimicking tooth development or physiological reparation have been applied to tooth regeneration studies, where the application of these nerve- or tooth-derived molecules has been proven effective. However, to date, basic studies in this field leave many vacancies to be filled. This literature review summarizes the recent advances in the basic studies on neural responses and regulation during tooth–periodontium development and homeostasis and points out some research gaps to instruct future studies. Deepening our understanding of the underlying mechanisms of tooth development and diseases will provide more clues for tooth regeneration.