A more precise definition of the term ‘skeletal muscle regeneration’ is required to reduce confusion and misconceptions. In this paper the term is used only for events that follow myofibre necrosis, to result in myogenesis and new muscle formation: other key events include early inflammation and revascularisation, and later fibrosis and re-innervation. The term ‘muscle regeneration’ is sometimes used casually for situations that do not involve myonecrosis; such as restoration of muscle mass by hypertrophy after atrophy, and other forms of damage to muscle tissue components. These situations are excluded from the definition in this paper which is focussed on mammalian muscles with the long-term aim of clinical translation to enhance new muscle formation after acute or chronic injury or during surgery to replace whole muscles. The paper briefly outlines the cellular events involved in myogenesis during development and post-natal muscle growth, discusses the role of satellite cells in mature normal muscles, and the likely incidence of myofibre necrosis/regeneration in healthy ageing mammals (even when subjected to exercise). The importance of the various components of regeneration is outlined to emphasise that problems in each of these aspects can influence overall new muscle formation; thus care is needed for correct interpretation of altered kinetics. Various markers used to identify regenerating myofibres are critically discussed and, since these can all occur in other conditions, caution is required for accurate interpretation of these cellular events. Finally, clinical situations are outlined where there is a need to enhance skeletal muscle regeneration: these include acute and chronic injuries or transplantation with bioengineering to form new muscles, therapeutic approaches to muscular dystrophies, and comment on proposed stem cell therapies to reduce age-related loss of muscle mass and function. This article is part of a directed issue entitled: Regenerative Medicine: the challenge of translation.