The system causing myofilament damage is separate from the phospholipase A2 pathway, Ca activation of which ultimately causes sarcolemma breakdown in muscle cells. Mitochondrial agents cause myofilament damage in saponin-skinned frog pectoris cutaneous muscle when [Ca] = 0. There are parallels with other systems that generate oxygen radicals. However, a variety of protectors against oxygen radicals, or anoxia, failed to protect; Ca-activated damage was not augmented by diethylthiocarbamate, nor was it accompanied by a respiratory burst. Thus, there is no firm evidence implicating oxygen radicals in myofilament damage. Thiol-oxidizing agents cause contraction damage in skinned muscle that resembles the quasirigor induced in myosin by N-ethylmaleimide. Activation of transmembrane dehydrogenases and electron flow produced damage and increased Ca sensitivity in skinned muscle, and it is suggested that this enzyme system may be implicated in characteristic damage to the myofilaments via redox cycling and modification of sulphydryl groups; its possible location on the sarcoplasmic reticulum is discussed.