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Cannabinoids have emerged in the last decades as promising therapeutic tools for the treatment of a wide range of neurological, metabolic or oncologic diseases, among others. These molecules mainly target the so-called CB1 and CB2 cannabinoid receptors, and/or the enzymes responsible for endocannabinoid biosynthesis and metabolism. However, other targets have been shown to modulate the actions of cannabinoids. These include ionotropic receptors, such as specific transient receptor potential channels; nuclear receptors, such as peroxisome proliferator-activated receptors or Class A orphan G protein-coupled receptors (GPCRs). In this chapter, we will provide an overview of cannabinoids actions regulated by their interaction with non-CB1, non-CB2 GPCRs such as the orphan receptors, GPR55, GPR18, or the GPR3–6–12 subset. Their activity at GPCRs from well-established families, including opioid, serotonin or adenosine receptors will also be analyzed. This body of research evidences the complex molecular pharmacology of cannabinoids and the need to fully unravel potential undesired off-target effects for the use of cannabinoid-based therapies.