The endogenous opioid and cannabinoid systems play major roles in the modulation of pain, mood, reward, and the development of addiction. Emerging research indicates that cannabinoids and opioids functionally interact at different levels. Of particular significance is the emerging clinical and preclinical evidence suggesting that the co-administration of cannabinoids and opioids may yield an opioid-sparing effect. This implies the potential for reducing opioid doses without compromising analgesic efficacy, offering a promising avenue for managing pain while mitigating the risks associated with high opioid dosages. However, preclinical research also indicates that some cannabinoids increase opioid-seeking behavior, complicating their co-administration for pain relief. Therefore, a better understanding of how these endogenous signaling systems interact in the brain is of significant interest. Several hypotheses have been formulated to explain this cross-modulation, including the release of opioid peptides by cannabinoids or endocannabinoids by opioids, as well as interactions at the receptor and/or signal transduction levels. Moreover, it is important to consider that the nature of cannabinoid and opioid interactions might differ in the brain circuits mediating reward and other pharmacological properties, such as antinociception. This chapter focuses on the potential interaction between the endogenous opioid and cannabinoid systems at the anatomical, cellular, and behavioral levels. We reviewed several mechanisms through which cannabinoids and opioids modulate reward, analgesia, and stress processing across diverse brain circuits. This comprehensive review aims to contribute to the current understanding of the complex interactions between these endogenous signaling systems, shedding light on potential therapeutic strategies and implications for clinical practice.