The attachment and removal of ubiquitin from substrate proteins can encode a wide range of signals, controlling cellular phenotypes from cell division to organelle abundance. But the complex genetics and many players involved in ubiquitin signaling have made it slow and difficult to decipher these functional networks. We are using next-generation genome editing and regulation technologies to gain molecular insight into ubiquitin-mediated signaling cascades involved in cellular homeostasis. For example, using unbiased screens with complex phenotypes, we are uncovering novel ubiquitin-related effectors that regulate processes such as human DNA repair and organelle autophagy. Endogenous tagging and editing approaches enable us to gain a deep understanding of the mechanisms by which these effectors encode and decode ubiquitin-mediated signals.