Skeletal muscle displays an impressive degree of plasticity. Exercise-induced adaptations in skeletal muscle structure and function underlie training and health-promoting effects. However, detailed mechanistic understanding of muscle plasticity is hampered by a poor knowledge of the role of the heterogenous cell types residing within the muscle microenvironment during and after exercise. We here combine a novel methodology for genome-wide transcriptome profiling of individual muscle fibers together with state-of-the-art single-cell and spatial omics approaches to evaluate the cell diversity in human skeletal muscle. This unprecedented detail in muscle cell diversity creates a new (third) layer of insight into our understanding of the exercise-induced muscle plasticity and its related health and performance implications.