The crucial role of the trace element selenium in livestock and human health, in particular in striated muscle function, has been well established but the underlying molecular mechanisms remain poorly understood. Over the last decade, identification of the full repertoire of selenium-containing proteins has opened the way towards a better characterization of these processes. Two selenoproteins have mainly been investigated in muscle, namely SelW and SelN. Here we address their involvement in muscle development and maintenance, through the characterization of various cellular or animal models. In particular, mutations in the SEPN1 gene encoding selenoprotein N (SelN) cause a group of neuromuscular disorders now referred to as SEPN1-related myopathy. Recent findings on the functional consequences of these mutations suggest an important contribution of SelN to the regulation of oxidative stress and calcium homeostasis. Importantly, the conclusions of these experiments have opened new avenues of investigations that provide grounds for the development of therapeutic approaches.