Upon exposure to external stressors, the body senses them and activates the sympathetic nervous system (SNS) to maintain the homeostasis, which is known as the “fight-or-flight” response. Recent studies have revealed that the SNS also plays pivotal roles in regulating immune responses, such as hematopoiesis, leukocyte mobilization, and inflammation. Indeed, overactivation of the SNS causes many inflammatory diseases, including cardiovascular diseases, metabolic disorders, and autoimmune diseases. However, the molecular basis essential for SNS-mediated immune regulation is not completely understood. In this review, we focus on axon guidance cues, semaphorins, which play multifaceted roles in neural and immune systems. We summarize the functions of semaphorins in the crosstalk between the SNS and the immune system, exploring its pathophysiological roles.