Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of common hepatic disorders in western countries, with multiple consequences and its incidence is paralleling the increasing numbers of overweight and obese individuals worldwide. The pathogenesis of NAFLD is thought to be related mainly with insulin resistance (IR) syndrome and oxidative stress; the latter resulting from mitochondrial fatty acids (FFAs) oxidation, nuclear factor-kappaB (NFκB)-dependent inflammatory cytokine expression and adipocytokines may promote hepatocellular damage, inflammation, fibrosis and progressive liver disease. Adipocytokines and other recognized cytokines produced partially by inflammatory cells infiltrating adipose tissue, play an important role in the pathogenesis of IR and NAFLD, through complex and interactive paracrine and endocrine mechanisms. Some adipocytokines, including adiponectin and leptin decrease IR, while others, including tumor necrosis factor (TNF)-α, interleukin (IL)-6 and resistin enhance IR. The multi-hit hypothesis provides a model that summarizes the complex factors and interactions leading from adipocytokines, FFAs metabolism and IR to NAFLD. This review outlines the pathways involved in adipocytokines, IR and NAFLD sequence; the first part describes the impaired IR pathway leading to NAFLD and the second part the mechanisms by which adipocytokines influence IR and NAFLD development and progression. Understanding these complex mechanisms has evoked new therapeutic approaches, which may provide promising results to date.