The receptor tyrosine kinases (RTKs) are a large family of cell-surface receptors, which are essential components of signal transduction pathways. There are more than fifty human RTKs that can be grouped into multiple RTK subfamilies. RTKs mediate cellular signaling transduction, and they play important roles in the regulation of numerous cellular processes. The dysregulation of RTK signaling is related to various human diseases, including cancers. The proteolytic cleavage phenomenon has frequently been found among multiple receptor tyrosine kinases. More and more information about proteolytic cleavage in RTKs has been discovered, providing rich insight. In this review, we summarize research about different aspects of RTK cleavage, including its relation to cancer, to better elucidate this phenomenon. This review also presents proteolytic cleavage in various members of the RTKs.