T cells play a crucial role in mediating adaptive immunity to infections, autoimmunity, and cancer. Upon immune challenge, T cells exit quiescence, undergo clonal expansion, and differentiate into effector cells, processes influenced by three established immune signals: antigen stimulation (Signal 1), costimulation (Signal 2), and cytokine signals (Signal 3). Emerging evidence highlights that nutrients, including glucose, amino acids, and lipids, are essential regulators of T cell responses, interacting with Signals 1–3 to shape T cell immunity. This review discusses the functional importance of nutrients as Signal 4, their mechanisms of transport, sensing, and signaling, and their roles in programming T cell differentiation and function. Nutrients influence T cell fate decisions, such as the differentiation of T helper (Th) subsets and memory cell formation, and can be targeted to improve disease therapy. Understanding how T cells respond to nutrient signals in various microenvironments provides insights into context-dependent functions of adaptive immunity and therapeutic interventions.T cells play a crucial role in mediating adaptive immunity to infections, autoimmunity, and cancer. Upon immune challenge, T cells exit quiescence, undergo clonal expansion, and differentiate into effector cells, processes influenced by three established immune signals: antigen stimulation (Signal 1), costimulation (Signal 2), and cytokine signals (Signal 3). Emerging evidence highlights that nutrients, including glucose, amino acids, and lipids, are essential regulators of T cell responses, interacting with Signals 1–3 to shape T cell immunity. This review discusses the functional importance of nutrients as Signal 4, their mechanisms of transport, sensing, and signaling, and their roles in programming T cell differentiation and function. Nutrients influence T cell fate decisions, such as the differentiation of T helper (Th) subsets and memory cell formation, and can be targeted to improve disease therapy. Understanding how T cells respond to nutrient signals in various microenvironments provides insights into context-dependent functions of adaptive immunity and therapeutic interventions.