Nitric oxide (NO) derivatives and reactive oxygen species (ROS) modulate contractile function of respiratory and limb skeletal muscle. The intracellular processes regulated by NO and ROS remain enigmatic, however. Studies of reduced preparations have identified a number of regulatory proteins that exhibit altered function when exposed to exogenous NO or ROS donors ex vivo. The relative importance of these targets in the intact cell is not known and conflicting theories abound regarding the mechanism(s) whereby NO and ROS regulate contraction. This review article provides a personal perspective on the processes regulated by NO and ROS by addressing three major topics: 1) the regulatory mechanisms by which endogenous NO depresses force production, 2) the processes whereby endogenous ROS modulate contraction of unfatigued muscle, and 3) the site(s) of action and reversibility of ROS effects in muscle fatigue.