The development of skeletal muscle is a highly regulated, multi-step process in which pluripotent mesodermal cells give rise to myoblasts that subsequently withdraw from the cell cycle and differentiate into myotubes as well as myofibers. The plasticity of myoblasts plays a critical role in maintaining skeletal muscle structure and function by myoblast activation, migration, adhesion, membrane reorganization, nuclear fusion, finally forming myotubes/myofibers. Our studies demonstrate that the local hypoxic microenvironment, a great diversity of regulatory factors such as IL-6 superfamily factors (IL-6, LIF, CNTF) and TGF-beta1 could regulate the myoblast plasticity. The aim of this paper is to review the previous studies focused on the regulation of myoblast plasticity and its mechanism in our laboratory. Knowledge about the microenvironment or factors involved in regulating the myoblast plasticity will help develop the prevention and cure measures of skeletal muscle diseases.