Heat shock protein 90 (Hsp90) is one of the central signal transduction regulators of the cell. Via client interactions with hundreds of proteins, including receptors, receptor regulatory kinases, and downstream signaling regulators, Hsp90 has a crucial and wide-ranging impact on signaling in response to numerous drugs with impacts on resultant physiology and behavior. Despite this importance, however, Hsp90 has barely been studied in the context of pain and the opioid receptor system, leaving open the possibility that Hsp90 could be manipulated to improve pain therapeutic outcomes, a current area of massive medical need. In this review, we will highlight the known roles of Hsp90 in directly regulating the initiation and maintenance of the pain state. We will also explore how Hsp90 regulates signaling and antinociceptive responses to opioid analgesic drugs, with a special emphasis on ERK MAPK signaling. Understanding this new and growing area will improve our understanding of how Hsp90 regulates signaling and physiology, and also may provide new ways to treat pain, and perhaps reduce the severe impact of the ongoing opioid addiction and overdose crisis.