Skeletal muscle injury, despite the initial trigger, leads to a stereotypical cascade of events mediated by cells of the immune system. Acute damage recruits cells of the innate immune system (polymorphonuclear leukocytes and monocytes/macrophages) that initially release noxious molecules and clear the cellular debris. Macrophages in particular display two distinct differentiation patterns. At early times after acute damage inflammatory macrophages are predominant, and play a non-redundant role in the clearance of cellular debris. At later time points, when fibre regeneration occurs, macrophages acquire a de-activated phenotype, which has been associated to tissue remodelling. A role for cells of the acquired immune system, in particular antigen-specific T and B cells, in muscle regeneration has been envisaged, but still needs to be elucidated. Similar events possibly play a role during persistent muscle damage in which fibres never completely heal. As a consequence infiltrating leukocytes stay alive and are continuously activated. Their effector function in situ contributes to perpetuate the damage and results in the deposition of collagen with interstitial fibrosis and fat accumulation. In this review we will discuss the events characterising acute and persistent damage in stretch-induced injury, autoimmune polymyositis, inclusion bodies myositis and muscular dystrophies. We will focus on the molecular interactions involved in the positive and negative regulation of the inflammatory damage, with specific attention to their exploitation in the context of strategies to limit muscle wasting and supporting fibre regeneration.