Genome integrity is vital to cellular homeostasis and its forfeiture is linked to deleterious consequences—cancer, immunodeficiency, genetic disorders and premature aging. The human ubiquitin ligase Pso4/Prp19 has emerged as a critical component of multiple DNA damage response (DDR) signaling networks. It not only senses DNA damage, binds double-stranded DNA in a sequence-independent manner, facilitates processing of damaged DNA, promotes DNA end joining, regulates replication protein A (RPA2) phosphorylation and ubiquitination at damaged DNA, but also regulates RNA splicing and mitotic spindle formation in its integral capacity as a scaffold for a multimeric core complex. Accordingly, by virtue of its regulatory and structural interactions with key proteins critical for genome integrity—DNA double-strand break (DSB) repair, DNA interstrand crosslink repair, repair of stalled replication forks and DNA end joining—it fills a unique niche in restoring genomic integrity after multiple types of DNA damage and thus has a vital role in maintaining chromatin integrity and cellular functions. These properties may underlie its ability to thwart replicative senescence and, not surprisingly, have been linked to the self-renewal and colony-forming ability of murine hematopoietic stem cells. This review highlights recent advances in hPso4 research that provides a fascinating glimpse into the pleiotropic activities of a ubiquitously expressed multifunctional E3 ubiquitin ligase.