Diagnostic precision, prediction and prevention of psychiatric disorders, including major unipolar depression, post-traumatic stress disorder (PTSD) and suicide ideation and attempts, remain underdeveloped areas in psychiatry given a general lack of biomarker assessment in the field. This makes the unmet goal of developing a precision medicine for these debilitating conditions an urgent necessity of neuropsychopharmacology research. Precision medicine, defined as “an emerging approach for treatment and prevention that takes each person's variability in genes, environment, and lifestyle” into account (1), will permit choosing the right treatment for the right person at the right time based on a unique individual neurobiologic biosignature. Indeed, it is anticipated that biomarker discovery will tremendously enhance refinement of individualized medicine that currently rely on subjective symptom assessment based on the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V). Both depression and PTSD are highly prevalent conditions affecting 3.4–12% of the general population and one of the main causes of disability. In the United States, pre-Covid suicide rates have increased by 25–30%, (from 10.5 to 13 per 100,000). These disorders share a number of symptoms and are highly comorbid. MDD is characterized by sadness, anhedonia, disturbed concentration, while PTSD symptoms include avoidance of traumatic memories, hyperarousal, hyperreactivity, flashbacks and nightmares. Antidepressant treatment with SSRIs (the gold standard for PTSD and depression) improves symptoms to about half of patients (2). Developing reliable biomarkers entails the promise of predicting the best treatments for subjects that are more likely to respond to an individually-designed rather than to a “one-fit-all” treatment. Biomarker discovery will also enhance diagnostic evaluation of patients who suffer from psychiatric disorders that share a large symptom overlap and prevalent disorder comorbidity. In recent years, several novel biomarker candidates for mood disorders have been suggested [reviewed in (3)]. The endocannabinoid system has received much interest owing its role in several physiological and pathophysiological functions, including regulation of emotional behavior, cognitive processes, inflammation, chronic pain, epilepsy, and in general, its role underlying neuropsychiatric disorders (4, 5). This opinion article will focus on the intriguing role of the endocannabinoid system in the regulation of affective disorders, specifically on major depressive disorders, PTSD and suicide behaviors. Furthermore, it will analyze whether data gathered in this exciting area of psychiatric research entails new leads in establishing novel biomarkers for these debilitating and prevalent psychiatric conditions that affect millions worldwide.