Skeletal muscle possesses a high plasticity and a remarkable regenerative capacity that relies mainly on muscle stem cells. Molecular and cellular components of the muscle stem cell niche, such as immune cells, play key roles to coordinate muscle stem cell function and to orchestrate muscle regeneration. An abnormal infiltration of immune cells and/or imbalance of pro- and anti-inflammatory cytokines could lead to muscle stem cell dysfunctions that could have long lasting effects on muscle function. Different genetic variants were shown to cause muscular dystrophies that intrinsically compromise muscle stem cell function and disturb their microenvironment leading to impaired muscle regeneration that contributes to disease progression. Alternatively, many acquired myopathies caused by comorbidities (e.g., cardiopulmonary or kidney diseases), chronic inflammation/infection, or side effects of different drugs can also perturb muscle stem cell function and their microenvironment. The goal of this review is to comprehensively summarize the current knowledge on acquired myopathies and their impact on MuSC function. We further describe potential therapeutic strategies to restore muscle stem cell regenerative capacity.