In past decades, type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease developed into a global public health disease with an endemic scale. Although up to now the pathogenesis of T2DM is still poorly understood, ectopic lipid accumulation is one of the strongest predictors for T2DM and is closely associated with insulin resistance.This review aims (i) to overview recent literature on the impact of intracellular lipid deposition, (ii) to point out changes in ectopic fat accumulation during diabetes progression or shortly after initializing individual therapy, and finally (iii) to expose unsolved questions and future perspectives in the role of ectopic lipids for the development of insulin resistance and T2DM.