Skeletal muscle is an endocrine organ that secretes a variety of compounds including proteins (myokines), metabolites, microRNAs (miRNAs), and exosomes, many of which are regulated by exercise and play important roles in endocrine signaling. Interorgan communication via muscle-secreted factors therefore provides a novel area for investigation and implicates the importance of skeletal muscle in the pathophysiology of metabolic diseases such as type 2 diabetes (T2D). Given that underlying molecular mechanisms of T2D are subject of ongoing research, in light of new evidence it is probable that interorgan cross-talk between skeletal muscle and pancreatic β-cells plays an important part. To date, the number of studies published in this field provide the basis of this review. Specifically, we discuss current experimental evidence in support for a role of skeletal muscle to β-cell cross-talk, paying particular attention to muscle-secreted factors including myokines, metabolites, miRNAs, and factors contained within exosomes that influence the function and/or the survival of β-cells in health and disease. In reviewing this evidence, we provide an update on the list of known muscle-secreted factors that have potential to influence the function and/or survival of β-cells under normal and diabetic conditions. We also report limitations of current cross-talk methods and discuss future directions in this growing field.