Excessive increased adipose tissue mass in obesity is associated with numerous co-morbid disorders including increased risk of type 2 diabetes, fatty liver disease, hypertension, dyslipidemia, cardiovascular diseases, dementia, airway disease and some cancers. The causal mechanisms explaining these associations are not fully understood. Adipose tissue is an active endocrine organ that secretes many adipokines, cytokines and releases metabolites. These biomolecules referred to as adipocytokines play a significant role in the regulation of whole-body energy homeostasis and metabolism by influencing and altering target tissues function. Understanding the mechanisms of adipocytokine actions represents a hot topic in obesity research. Among several secreted bioactive signalling molecules from adipose tissue and liver, retinol-binding protein 4 (RBP4) has been associated with systemic insulin resistance, dyslipidemia, type 2 diabetes and other metabolic diseases. Here, we aim to review and discuss the current knowledge on RBP4 with a focus on its role in the pathogenesis of obesity comorbid diseases.