Kindlin-2 functions in the maintenance of homeostasis and in human diseases. This study investigated the interrelationship between Kindlin-2 expression in tissues and the corresponding germ layers from which these tissues originated. Kindlin-2 expression was examined in normal adult human organs and human cancer tissues by immunohistochemical analyses. Analysis of Kindlin-2 mRNA levels in adult human organs in the Oncomine dataset revealed Kindlin-2 is highly expressed in mesoderm-derived organs. However, Kindlin-2 was negative or weakly expressed in endoderm/ectoderm-derived organs. Interestingly, the abnormal expression of Kindlin-2 was observed in a variety of human cancers. In agreement with its expression profile in humans, Kindlin-2 was also highly expressed in mesoderm-derived organs in mouse embryos with the exception of strong Kindlin-2 expression in ectoderm-derived spinal cord and ganglia, tissues that are highly mobile during embryonic development. Importantly, we demonstrated the expression level of Kindlin-2 in adult organs correlated with their embryonic dermal origins and deregulation of Kindlin-2 in tissues is associated with tumor progression. This finding will help us understand the dual role of Kindlin-2 in the regulation of tumor progression and embryonic development.