<p>Ubiquitin-dependent protein degradation regulates myriad fundamental cellular processes. At its core are degradation signals, or degrons, that initiate substrate engagement and ubiquitination by E3 ubiquitin ligases. Here we highlight how a variety of degradation signals promote substrate–E3 ligase interactions to orchestrate protein turnover with precision. While short linear motifs are frequently identified as degrons, an increasing number of degrons have recently been mapped to high-order protein structures, underscoring the architectural diversity and cryptic nature of degradation signals. Furthermore, nonproteinaceous signals beyond degrons often facilitate the precise control of protein ubiquitination. These additional signals can reside within substrates and E3 ligases or at their interfaces. Finally, we discuss how dysregulation of degrons and degradation signals is linked to human diseases. A deeper mechanistic understanding of degradation signals will guide new therapeutic strategies, whether by restoring defective protein ubiquitination or by harnessing targeted protein degradation.</p><p></p>