Tooth formation is a complex and multifaceted biological process, intricately regulated by a diverse array of molecular entities and signaling pathways. Within this context, amelogenesis specifically refers to the development of enamel, an essential structure that provides protection and structural integrity to teeth. During amelogenesis, various mediators of the immune response, including transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α), and c-Jun N-terminal kinase (JNK), play critical roles. Disruptions occurring during the crucial secretion and biomineralization phases of enamel development can lead to a spectrum of dental enamel defects, which are often characterized by structural anomalies. The etiology of these defects is inherently complex and multifactorial, encompassing genetic predispositions, systemic influences, and local environmental factors, which may act individually or in combination to contribute to the adverse outcomes observed. Recent investigations have begun to uncover the significant influence of immune response mechanisms on amelogenesis, suggesting that these immunological factors may play a substantial role in the pathogenesis of dental enamel defects. This chapter aims to elucidate the diverse roles of specific components of the immune system in the context of dental enamel development. Furthermore, it explores the intricate interactions between various molecular mediators and signaling pathways, detailing their collective influence on amelogenesis. A thorough understanding of the interplay between immunological factors and tooth development is critical for advancing the frontiers of diagnostic and therapeutic strategies. Such insights may pave the way for innovative approaches to address enamel defects and enhance oral health outcomes in affected individuals.