Posttranscriptional modifications of proteins by the ubiquitin and SUMO (Small Ubiquitin-related Modifier) pathways regulate the function of protein networks, enable cells to respond to signaling cues during development, and to cope with the changing environment during adult life. Both modifications can impact protein stability, localization, protein-protein interactions and/or function. While both pathways have been well studied individually, the long-speculated nature of crosstalk between SUMO and ubiquitin pathways has been molecularly enigmatic. Recent work in yeast and mammalian cells identified the connection between the two pathways in the form of a conserved family of RING finger ubiquitin ligases termed SUMO-Targeted ubiquitin ligases (STUbLs). These proteins bind to SUMOylated substrates via their SUMO interaction motif and subsequently target them for ubiquitylation. Characterization of Degringolade (Dgrn), a STUbL gene in the fly genome, enabled us to evaluate the contribution of STUbLs to the development of multi-cellular organisms. Analysis of dgrn mutants showed that they are required for cyto-nuclear organization during early embryonic development, and are likely required to cope with mitotic stress and DNA damage. Furthermore, in transcription, STUbLs regulate protein-protein interactions, and are part of molecular machinery that regulates co-repressor choice and gene-expression selectivity during development.