The human brain is an energetically costly organ, consuming 20–25% of all biochemical energy produced in the body, despite comprising only 2–3% of total body mass. Most energy in the brain is consumed to support synaptic neurotransmission, which is the primary means of neuron-to-neuron communication between. This energy is in the form of adenosine triphosphate (ATP), and within neural cells, nearly all ATP is produced by mitochondria via the process of oxidative phosphorylation (OXPHOS). To ensure that ATP is readily available, mitochondria are trafficked to areas of greater energy use, such as neuronal synapses. The balance between energetic supply and synaptic communication is essential for proper brain functioning. This chapter begins with a brief introduction to key features of neuronal synapses and mitochondrial energy production in the cerebral cortex. Next, the tight and bidirectional coupling of neuronal synaptic activity and mitochondrial OXPHOS is examined from functional, ultrastructural, and molecular perspectives. The effects of brain and non-brain organ system perturbations on synaptic-mitochondrial coupling are then examined within the context of (1) primary brain disorders, such as schizophrenia and bipolar disorder, and (2) primary peripheral disorders, such as diabetes and obesity. Finally, a discussion of potential intervention strategies that may restore neural communication and mitochondrial bioenergetics, within the framework of the brain-body connection, is provided.