The practical basis for massive parallel sequencing is described to help clinicians in choosing the most adequate diagnostic approach for childhood myopathies. The key quality feature for massive parallel sequencing is the sequence depth (coverage) as a prerequisite for variant identification and quantification of sequence copy numbers. Our experience with a next-generation sequencing gene panel for the analysis of muscular dystrophies/myopathies with infantile or juvenile onset resulted in the identification of pathogenic or likely pathogenic mutations in approximately 41% (of 141 patients), thus leading to a definitive diagnosis. A subset of patients shows an accumulation of “excess” heterozygous variants that may act as modifiers of the phenotype. Massive parallel sequencing has become a reliable and cost-effective method, but it requires exact clinical, bioptic, and/or radiologic information to evaluate the clinical relevance of possibly pathologic variants.