Prevalence of Type 2 Diabetes Mellitus (T2DM) has reached pandemic levels in Western societies. T2DM begins with the development of peripheral insulin resistance which prior research suggests may commonly originate within skeletal muscle. A number of mechanisms have been proposed for the development of muscle insulin resistance including those of classical glucose handling, but also other cellular derangements observed in this disease which include mitochondrial degeneration, alterations in muscle protein turnover and early evidences for dysregulation of microRNAs. The purpose of the current review is to examine current findings on these latter aspects of mitochondrial maintenance, protein turnover and microRNA dysregulation along with the potential implications for these derangements in the development of insulin resistance and hence T2DM. We summarize multiple evidences for the degeneration of mitochondria and known elements of the processes regulating mitochondrial quality. Subsequently, we examine current findings of alterations in muscle protein synthesis and autophagic protein degradation in T2DM and potential feedback of these systems onto canonical insulin signaling. Finally, evidences are emerging for the dysregulation of microRNAs in muscle insulin resistance. Of note early data point to several microRNAs altered by the insulin resistant state which exhibit relations to classic insulin signaling and the other processes discussed here. Considering that T2DM may be initiated with muscle insulin resistance, improved understanding of the dysregulation of these metabolic parameters of skeletal muscle in the pathogenesis of T2DM may be key to develop efficacious therapeutic modalities to prevent and treat this condition.