Non-alcoholic fatty liver disease (NAFLD) is associated with diabetes, obesity and insulin resistance. The pathogenesis of NAFLD is complex, but modulation of the activities of transcription factors that regulate hepatic lipid and glucose homeostasis may be a key to treating NAFLD. An example of a key transcription factor regulating hepatic lipid metabolism is sterol regulatory element binding proteins (SREBPs), and in this review we present evidence supporting a key role for SREBPs in NAFLD. Currently, the only effective treatment for NAFLD is caloric restriction and peroxisome proliferator activated receptor (PPAR-γ) agonists. We suggest that further studies are urgently needed to evaluate modulation of SREBP activity as a potential new treatment for NAFLD.