Organisms must distribute sufficient energy among different and often competing physiological systems. This task can become challenging, however, as resources are often limiting, resulting in energetic trade-offs. For example, energetically based trade-offs between the reproductive and immune systems are common across taxa, yet the regulatory mechanisms underlying these trade-offs remain unclear. The adipose tissue hormone leptin is an ideal candidate for the modulation of energetic trade-offs between different physiological systems as this hormone serves as a gage of fat reserves and also modulates a range of physiological activities including the reproductive and immune processes. This article presents a review of the evidence for the role of leptin as a modulator of energetic trade-offs with the immune system and suggests its importance in disease ecology. In addition, we provide a case study of the ornate tree lizard (Urosaurus ornatus), testing whether leptin is involved in mediating a well-documented influence of energy state on the trade-off between reproductive activity and immune function. Overall, the combined results suggest that leptin serves as a proximate endocrine signal of available energy to the immune system, and therefore likely to affect susceptibility to diseases.