Abstract: Rationale：Marijuana is the most commonly used illicit drug in the United States with recent surveys estimating over 22 million current users. However，there is growing acceptance of its recreational use，evident by successful efforts to decriminalize and，in some states，legalize use. In addition，although the full medicinal value of cannabis is not yet understood，such cannabinergic effects are of known benefit in the palliative care of anorectic patients undergoing chemotherapy or suffering debilitating conditions such as AIDS or Alzheimer’s disease and，as well，may be an effective analgesic under certain painful conditions. Objective：This current state of affairs has led to a broadening interest in the clinical utility of drugs that target the endocannabinoid system. In this regard，however，delta-9- tetrahydrocannabinol （THC），the primary psychoactive ingredient in marijuana，is generally acknowledged to produce some unwanted effects in humans. These include deleterious effects on several types of complex behavior，especially related to learning，memory，and vigilance. Unfortunately，synthetic cannabinoid agonists appear to share these adverse side effect profiles. Recently，however，a greater understanding has developed of the two primary endocannabinoid neurotransmitters，anandamide and 2-arachidonoylglycerol （2-AG） and，as well，ligands that inhibit the activity of fatty acid amide hydrolase （FAAH） and monoacylglycerol lipase （MGL）， which can indirectly increase the concentrations of，respectively，anandamide and 2-AG. Methods：Employing operant techniques in nonhuman primates such as drug discrimination， emetic observation，nociception assays，and touchscreen-based models of learning and memory，this presentation will highlight recent advances in the understanding of THC’s effects on complex behavioral processes and，as well，efforts to develop drugs that engage the cannabinergic system and retain medicinal value，yet produce lesser adverse psychoactive effects. Results：Synthetic and phyto-cannabinoids produce highly consistent effects on most behavioral endpoints despite efficacy differences identified in vitro. However，engaging the endogenous cannabinoid system，either via exogenous administration of endocannabinoids or indirect endocannabinoid elevation via inhibition of catabolic enzyme inhibition，produced lesser disruptive effects on cognitive behavior with similar effectiveness of medicinal endpoints （e.g.，analgesia and emesis）. Conclusion：Engagement of the endogenous cannabinoid system via endocannabinoid administration or indirect elevation via FAAH and/or MGL inhibition may represent a therapeutic advantage in clinical settings relative to THC or other typical cannabinoid agonists.