Due to the legalization of marijuana and the increased demand for cannabis and alcohol consumption, research efforts highlighting the biomedical consequences of the use of alcohol and cannabinoids are not only relevant to the substance abuse scientific field, but are also of public health interest. Moreover, an overview of the recent literature about alcohol and cannabinoids neuro-immunomodulatory effects highlighting their future therapeutic potentials will provide a significant contribution to science and medicine. Therefore, in the current review, we will first discuss briefly the prevalence of alcohol and marijuana abuse, followed by a discussion on the individual effects of alcohol and cannabinoids on the immune system; then, we will focus on the role of endo-cannabinoids on the alcohol-induced inflammatory effects. The final section will highlight the therapeutic potential of cannabinoid receptors and the novel strategies to treat alcohol dependence as determined by in vitro, in vivo and clinical studies. In addition, the review also incorporates cytokine array data obtained from human Monocyte-Derived Dendritic Cells, providing a different perspective on the alcohol and cannabinoid abuse divergent effects on cytokine production. The ultimate objective of the current review is a discussion of the individual effects of alcohol and marijuana abuse on inflammation and the combined effects of alcohol consumption and cannabinoid receptor signaling leading to the understanding of novel therapeutic strategies to treat alcohol dependence using cannabinoid receptor targeting.