Deregulation of growth factor receptor tyrosine kinases (RTKs) is linked to a large number of malignancies. This occurs through a variety of mechanisms that result in enhanced activity of the receptor. Considerable evidence now supports the idea that loss of negative regulation plays an important role in receptor deregulation. RTKs are removed from the cell surface via endocytosis and many are subsequently degraded in the lysosome. Lysosomal targeting has recently been linked with receptor ubiquitination. We review here molecular alterations that uncouple RTKs from ubiquitination and implicate loss of ubiquitination as a process that plays a significant role in the pathogenesis of cancer.