Polysubstance use makes up a majority of drug use, yet relatively few studies investigate the abuse-related effects of drug mixtures. Dose-addition analyses provide a rigorous and quantitative method to determine the nature of the interaction (i.e., supraadditive, additive, or subadditive) between two or more drugs. As briefly reviewed here, studies in rhesus monkeys have applied dose-addition analyses to group level data to characterize the nature of the interaction between the reinforcing effects of stimulants and opioids (e.g., mixtures of cocaine + heroin). Building upon these foundational studies, more recent work has applied dose-addition analyses to better understand the nature of the interaction between caffeine and illicit stimulants such as MDPV and methamphetamine in rats. In addition to utilizing a variety of operant procedures, including drug discrimination, drug self-administration, and drug-primed reinstatement, these studies have incorporated potency and effectiveness ratios as a method for both statistical analysis and visualization of departures from additivity at both the group and individual subject level. As such, dose-addition analyses represent a powerful and underutilized approach to quantify the nature of drug–drug interactions that can be applied to a variety of abuse-related endpoints in order to better understand the behavioral pharmacology of polysubstance use.