ATP and glutamate have emerged as highly versatile molecules for cellular metabolism and intercellular communication in the brain. Their metabolic and signaling pathways are interlaced. We concisely outline the synthesis and metabolism of these precious molecules, as well as their use as neurotransmitters in autocrine, paracrine, and heterocellular signaling. Functional diversity of this glutamatergic and purinergic signaling is defined by an expression of a multitude of receptors on neurons and glial cells alike. Both ATP and glutamate play a role in neuropathology. This chapter is meant to introduce the chapters that follow in this book dedicated to the in-depth overview of the role of glutamate and ATP in the brain metabolism and signaling in health and disease.