Helper CD4⁺ T cells differentiate into distinct subsets with unique cytokine profiles, crucial for immune defense and disease. Recent research challenges the traditional view of these subsets as fixed lineages, suggesting they may be more plastic. This review discusses mechanisms underlying commitment and plasticity of helper CD4⁺ T cells, their therapeutic implications, and the complexity of their differentiation. CD4⁺ T cells, upon encountering pathogens, differentiate into subsets like Th1, Th2, Tregs, Th17, and Tfh, each with distinct functions. However, evidence shows that these subsets can change their cytokine production, indicating plasticity. Master regulators like Foxp3, T-bet, GATA3, and Rorγt influence lineage commitment, but their expression is not fixed. Epigenetic modifications and microRNAs also play roles in regulating gene expression and cell fate. The concept of stable lineages is being reevaluated, as cells can switch between states. Understanding these mechanisms is vital for developing therapies for autoimmune and allergic diseases. Future research aims to clarify the dynamic nature of T cell differentiation and the interplay between transcription factors, epigenetic modifications, and miRNAs. Advances in technology and computational methods will help unravel the complexity of T cell biology and its implications for disease treatment.Helper CD4⁺ T cells differentiate into distinct subsets with unique cytokine profiles, crucial for immune defense and disease. Recent research challenges the traditional view of these subsets as fixed lineages, suggesting they may be more plastic. This review discusses mechanisms underlying commitment and plasticity of helper CD4⁺ T cells, their therapeutic implications, and the complexity of their differentiation. CD4⁺ T cells, upon encountering pathogens, differentiate into subsets like Th1, Th2, Tregs, Th17, and Tfh, each with distinct functions. However, evidence shows that these subsets can change their cytokine production, indicating plasticity. Master regulators like Foxp3, T-bet, GATA3, and Rorγt influence lineage commitment, but their expression is not fixed. Epigenetic modifications and microRNAs also play roles in regulating gene expression and cell fate. The concept of stable lineages is being reevaluated, as cells can switch between states. Understanding these mechanisms is vital for developing therapies for autoimmune and allergic diseases. Future research aims to clarify the dynamic nature of T cell differentiation and the interplay between transcription factors, epigenetic modifications, and miRNAs. Advances in technology and computational methods will help unravel the complexity of T cell biology and its implications for disease treatment.