Nonalcoholic fatty liver disease (NAFLD) has emerged as a significant public health problem. Besides the liver, NAFLD is also associated with increased cardiovascular and overall morbidity and mortality. NAFLD warrants intensive research, because no treatment has been established as yet. This may be partly attributed to the fact that the majority of the relative clinical trials have a monotherapeutic direction. However, the multifactorial pathogenesis of NAFLD may probably direct clinical trials to a combined therapeutic approach. The aim of this review is to provide a description of the multifactorial pathogenesis of NAFLD and type II diabetes mellitus-NAFLD interplay, and to summarize the therapeutic trials focusing on the combined NAFLD treatment, providing a link between the multiple-hit pathogenesis and the multimodal treatment of NAFLD patients. A diabetes-like therapeutic approach for NAFLD is finally proposed.