The etiology of obesity-induced skeletal muscle insulin resistance remains elusive. Several molecular mechanisms have been proposed as link between metabolic alterations and decreased cell insulin response. Obesity has been linked to increases in skeletal muscle ectopic accumulation of lipid and decreases in skeletal muscle mitochondrial content. However, the athlete paradox clearly shows that skeletal muscle with high lipid accumulation can be very responsive to insulin. During the last years our group has investigated whether the combination of qualitative and quantitative measurements of skeletal muscle lipid storage and mitochondrial networks can explain changes in skeletal muscle insulin sensitivity in a morbid obese population undergoing gastric-by-pass. Several high resolution microscopy techniques have been used for the qualitative measurements of both lipid storage and mitochondrial dynamics.