Opioid abuse continues to be a significant public health challenge, with rates of opioid-related overdose deaths increasing continuously over the last two decades. There also has been a sharp increase in overdose deaths involving stimulant drugs, primarily cocaine and methamphetamine. Recent estimates indicate a high prevalence of co-use of opioids and stimulants, which is a particularly complex problem. Behavioral pharmacology research over the last few decades has characterized interactions between opioids and stimulants as well as evaluated potential treatments. This chapter describes interactions between opioids and stimulants, with a focus on pre-clinical studies of abuse-related behavioral effects using self-administration, reinstatement, drug discrimination, place conditioning, and intracranial self-stimulation paradigms in laboratory animals. In general, the literature provides substantial evidence of mutual enhancement between opioids and stimulants for abuse-related effects, although such results are not ubiquitous. Enhanced abuse-related effects could manifest in many ways including engaging in drug seeking and taking behaviors with greater persistence, effort, and motivation and/or increased likelihood of relapse. Moreover, studies on opioid/stimulant combinations set the stage for evaluating potential treatments for polysubstance use. Behavioral pharmacology research has proven invaluable for elucidating these relationships using rigorous experimental designs and quantitative analyses of pharmacological and behavioral data.