Skeletal muscle tissue is highly metabolically active and yields wastes that the kidneys must excrete to maintain a homeostatic internal environment. Cross-communications between muscles and other organs participate in most physiological and pathological events and are responsible for the maintenance of homeostasis. Here, we present an overview of the main studied myokines, which have been defined as cytokines and other peptides that are produced, expressed, and released by muscle fibers in response to muscular contractions, and exert either autocrine, paracrine, or endocrine effects; their principal function in the crosstalk between muscle and kidney will be summarized. Furthermore, we will describe the factors mediating such crosstalk and review the mechanisms involved in the development of potentially-associated diseases, with a particular regard to critically ill patients. These connections are shedding new light on the pathogenesis of systemic diseases and will likely provide novel potential targets for the treatment of systemic diseases.