Skeletal muscle weakness is an important feature of numerous pathological conditions and it may also be a component in normal ageing. Decreased muscular strength can be due to decreased muscle mass and/or intrinsic defects in the muscle cells. In this chapter we will discuss decreased force production due to mechanisms intrinsic to skeletal muscle cells. We will mainly use data from mouse disease models to exemplify defects at various sites in the cellular activation-contraction pathway. We will show that depending on the underlying problem, muscle weakness can be due decreased Ca2+ release from the sarcoplasmic reticulum, reduced myofibrillar Ca2+ sensitivity and/or decreased ability of the cross-bridges to generate force.