The level of transcription factors is tightly controlled by their rates of synthesis and degradation. Many critical factors are maintained at an appropriate level by targeted addition of ubiquitin and degradation via the proteasome. Whereas ubiquitination targets modified proteins for degradation, modification of substrates by the family of ubiquitin-like proteins does not target the proteins for degradation but can alter the stability and other properties of the modified proteins. Here we discuss the elaborate mechanisms that have evolved to allow specific recognition of substrates targeted for modification. Specific examples are discussed to illustrate the different mechanisms involved and the importance of regulated degradation in diseases such as cancer.