Critically ill patients with sepsis require a multidisciplinary approach, as this situation implies multiorgan distress, with most of the bodily biochemical and cellular systems being affected by the condition. Moreover, sepsis is characterized by a multitude of biochemical interactions and by dynamic changes of the immune system. At the moment, there is a gap in our understanding of the cellular, genetic, and molecular mechanisms involved in sepsis. One of the systems intensely studied in recent years is the endocannabinoid signaling pathway, as light was shed over a series of important interactions of cannabinoid receptors with biochemical pathways, specifically for sepsis. Furthermore, a series of important implications on inflammation and the immune system that are induced by the activity of cannabinoid receptors stimulated by the delta-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) have been noticed. One of the most important is their ability to reduce the biosynthesis of pro-inflammatory mediators and the modulation of immune mechanisms. Different studies have reported that cannabinoids can reduce oxidative stress at mitochondrial and cellular levelsThe aim of this review paper was to present, in detail, the important mechanisms modulated by the endocannabinoid signaling pathway, as well as of the molecular and cellular links it has with sepsis. At the same time, we wish to present the possible implications of cannabinoids in the most important biological pathways involved in sepsis, such as inflammation, redox activity, immune system, and epigenetic expression. cascade and in the evolution of sepsis are represented by the inflammatory response, immune response, and redox activity, followed by the involvement of cellular defects, which all lead to severe organ dysfunction. Adding to this phenomenon are severe respiratory infections; tissue hypoxia; acute kidney injury (AKI); metabolic imbalances; and, last but not least, derangements of the biological system as a whole. Through the augmentation of the inflammatory status and through the concomitant derangement of several organ functions, a high percentage of critical patients with sepsis develop multiple organ dysfunction syndrome (MODS), and finally death [8,[10][11][12].Numerous biochemical and cellular systems involved in sepsis pathogenesis have been studied, both in order to better understand these complex mechanisms, and in the hope of finding new therapeutic targets. The endocannabinoid response system is one of them. Recent studies have shown the involvement of specific endocannabinoid receptors, such as endocannabinoid CB1 receptor and CB2 receptor, as well as their link with important processes in sepsis, such as the immune response, inflammatory response, and redox activity [13]. Furthermore, a series of implications on the epigenetic processes have also been proven, through the change in the microRNAs expression, the microRNAs responsible for the modulation of the immune, and inflammatory systems [14]. It was also shown that by stimulatin...