How loss- or gain-of-function for a gene in skeletal muscle induces muscle phenotypes is an important topic. Two important underlying rationales are: (a) understanding the fundamentals of gene regulations in the skeletal muscle and (b) how they influence physiological and metabolic functions. The knowledge of gene functions in the skeletal muscle is crucial to target the selection of interventions that will promote muscle health, prevent muscle loss, and treat muscle diseases. This chapter briefly introduces current techniques, such as the Cre-LoxP system, and its application with muscle-specific gene promoters. These advances in studying skeletal muscle-specific gene manipulations in animal models consequently broadened our views of muscle phenotypes related to gene regulations. We then summarize some current findings in gene manipulations regarding muscle mass, fiber-type shifting, metabolism, muscle diseases, and exercise performance. Lastly, we discuss the precautions and future directions from the current knowledge. We anticipate that by using numerous examples in this chapter, readers could understand the concepts of genetic engineering contributing to altered skeletal muscle phenotype.