Purpose This review aimed to discuss the conflicting findings from resistin research in rodents and humans as well as recent advances in our understanding of resistin’s role in obesity and insulin resistance. Methods A comprehensive review and synthesis of resistin’s role in obesity and insulin resistance as well as conflicting findings from resistin research in rodents and humans. Results In rodents, resistin is increased in high-fat/high-carbohydrate-fed, obese states characterized by impaired glucose uptake and insulin sensitivity. Resistin plays a causative role in the development of insulin resistance in rodents via 5′ AMP-activated protein kinase (AMPK)-dependent and AMPK-independent suppressor of cytokine signaling-3 (SOCS-3) signaling. In contrast to rodents, human resistin is primarily secreted by peripheral-blood mononuclear cells (PBMCs) as opposed to white adipocytes. Circulating resistin levels have been positively associated with central/visceral obesity (but not BMI) as well as insulin resistance, while other studies show no such association. Human resistin has a role in pro-inflammatory processes that have been conclusively associated with obesity and insulin resistance. PBMCs, as well as vascular cells, have been identified as the primary targets of resistin’s pro-inflammatory activity via nuclear factor-κB (NF-κB, p50/p65) and other signaling pathways. Conclusion Mounting evidence reveals a continuing disconnect between resistin’s role in rodents and humans due to significant differences between these two species with respect to resistin’s gene and protein structure, differential gene regulation, tissue-specific distribution, and insulin resistance induction as well as a paucity of evidence regarding the resistin receptor and downstream signaling mechanisms of action.