CD4 T cells play crucial roles in adaptive immunity, autoimmunity, asthma, allergic responses, and tumor immunity. Naive CD4 T cells can differentiate into various lineages of T helper (Th) cells, including Th1, Th2, Th17, and iTreg, based on their cytokine production and function. This review summarizes the discovery, functions, and relationships among Th cells, the cytokine and signaling requirements for their development, the transcription factors involved in their differentiation, the epigenetic regulation of key cytokines and transcription factors, and human diseases involving defective CD4 T cell differentiation. The cytokine environment plays a central role in determining the fate and function of CD4 effector/regulatory subpopulations, with the induction of distinct patterns of gene expression achieved through various mechanisms. The master transcription factors and STAT proteins are essential for Th cell fate determination and cytokine production, and they collaborate to regulate the production of key cytokines. Other transcription factors, such as Runx, IRF, Gfi-1, Ikaros, and c-Maf, also play important roles in fine-tuning Th cell differentiation. The collaboration between transcription factors, such as GATA3 and STAT5, T-bet and STAT4, RORγt and STAT3, and cross-regulation among transcription factors during Th cell differentiation are discussed.CD4 T cells play crucial roles in adaptive immunity, autoimmunity, asthma, allergic responses, and tumor immunity. Naive CD4 T cells can differentiate into various lineages of T helper (Th) cells, including Th1, Th2, Th17, and iTreg, based on their cytokine production and function. This review summarizes the discovery, functions, and relationships among Th cells, the cytokine and signaling requirements for their development, the transcription factors involved in their differentiation, the epigenetic regulation of key cytokines and transcription factors, and human diseases involving defective CD4 T cell differentiation. The cytokine environment plays a central role in determining the fate and function of CD4 effector/regulatory subpopulations, with the induction of distinct patterns of gene expression achieved through various mechanisms. The master transcription factors and STAT proteins are essential for Th cell fate determination and cytokine production, and they collaborate to regulate the production of key cytokines. Other transcription factors, such as Runx, IRF, Gfi-1, Ikaros, and c-Maf, also play important roles in fine-tuning Th cell differentiation. The collaboration between transcription factors, such as GATA3 and STAT5, T-bet and STAT4, RORγt and STAT3, and cross-regulation among transcription factors during Th cell differentiation are discussed.