Endocannabinoids acting via CB₁ receptors (CB₁R) play a critical role in regulating energy homeostasis, which was the rationale for the pharmaceutical development of CB₁R antagonists for the treatment of obesity. Although the first-in-class CB₁R antagonist rimonabant proved to be effective in mitigating obesity and its multiple cardiometabolic complications, it was withdrawn from clinical use due to CNS-mediated neuropsychiatric side effects, which halted the further therapeutic development of the whole class of these compounds. Compared to the brain, CB₁Rs are expressed at low yet functional levels in peripheral organs involved in regulating energy homeostasis, including liver, skeletal muscle, adipose tissue and endocrine pancreas. In recent preclinical studies, selective targeting of these receptors by ‘second generation’ peripherally restricted CB₁R antagonists replicated the metabolic benefits of rimonabant in rodent models of obesity and diabetes without causing CNS-mediated side effects. Increased CB₁R activity also contributes to complex, multifactorial disorders such as various forms of tissue fibrosis, treatment of which may benefit from simultaneous engagement of more than one therapeutic target. Accordingly, novel ‘third generation’ hybrid inhibitors of peripheral CB₁R and inducible NO synthase were tested in mouse models of liver and pulmonary fibrosis where their antifibrotic efficacy was found to exceed the efficacy of drugs that inhibit only one of these targets. In this review, we will discuss the challenges and opportunities offered by second and third generation CB₁R antagonists and their potential therapeutic uses.