Significant limitations with the currently available antidepressant treatment strategies have inspired research on finding new and more efficient drugs to treat depression. Cannabidiol (CBD) is a non-psychotomimetic component of Cannabis sativa and preclinical evidence suggests it can be a promising new antidepressant. The first evidence on CBD antidepressive properties were showed ten years ago and it has been confirmed by several other groups since then. More recent studies have shown that CBD promotes rapid and a sustained antidepressant effect in different animal models. Such effects seem to involve increased Brain Derived Neurotrophic Factor (BDNF) signaling in limbic brain regions important for stress adaptation and depression neurobiology, resulting in increased synaptogenesis and neurogenesis. CBD has a complex pharmacology, with the ability to interact with multiple neurotransmitter systems involved in depression, including the serotonergic, glutamatergic, and endocannabinoid systems. It is not yet clear how these mechanisms are integrated to promote the molecular and behavioral effects induced by CBD. Despite evidence from animal studies, there is currently insufficient evidence from human studies to support that CBD could promote mood improving effects in depressed patients. Nevertheless, this book chapter reviews and discusses the current evidence and highlights need of more investigation on the putative antidepressant effect induced by CBD.