Electrophysiological approaches provide powerful tools to further our understanding of how different opioids affect signaling through opioid receptors; how opioid receptors modulate circuitry involved in processes such as pain, respiration, addiction and feeding; and how receptor signaling and circuits are altered by physiological challenges such as injury, stress and chronic opioid treatment. The use of genetic manipulations to alter or remove mu opioid receptors (MORs) with anatomical and cell-type specificity and the ability to activate or inhibit specific circuits through opto- or chemo-genetic approaches are being used in combination of electrophysiological, pharmacological, and systems-level physiology experiments to expand our understanding of the beneficial and mal-adaptive roles of opioids and opioid receptor signaling. New approaches for studying endogenous opioid peptide signaling and release and the dynamics of these systems in response to chronic opioid use, pain and stress will add another layer to our understanding of the intricacies of opioid modulation of brain circuits. This understanding will lead to new targets or approaches for drug development or treatment regimens that may affect both acute and long-term effects of manipulating the activity of circuits involved in opioid-mediated physiology and behaviors. This review will discuss recent advancements in our understanding of the role of phosphorylation in regulating MOR signaling as well as our understanding of circuits and signaling pathways mediating physiological behaviors such as respiratory control and discuss how electrophysiological tools combined with new technologies have and will continue to advance the field of opioid research. SIGNIFICANCE STATEMENT: This review discusses recent advancements in our understanding of mu opioid receptor function and regulation and the role of electrophysiological approaches combined with new technologies in pushing the field of opioid research forward. This covers regulation of MOR at the receptor level, adaptations induced by chronic opioid treatment, sites of action of MOR modulation of specific brain circuits and the role of the endogenous opioid system in driving physiology and behavior through modulation of these brain circuits.