In humans, more than 200 different mutations within seven genes that encode thin filament proteins have been identified. These mutations have been linked to skeletal muscle weakness and to various congenital myopathies. By studying the structural and functional effects of these mutations, many recent studies have deciphered novel roles for thin filament proteins in the regulation of skeletal muscle physiology. In the present seminar, I will present these studies that use human skeletal muscle biopsy specimen samples and particular methodological approaches.