Covalent attachment of the ubiquitin-related protein SUMO to other proteins participates in many processes including signal transduction, transcriptional regulation, and growth control. We report the characterization of Siz1 as an E3-like factor in the SUMO pathway. Siz1 is required for SUMO attachment to the S. cerevisiae septins in vivo and strongly stimulates septin sumoylation in vitro. Siz1 and the related protein Siz2 promote SUMO conjugation to different substrates at different stages of the cell cycle and, together, are required for most SUMO conjugation in yeast. Siz1, Siz2, and the PIAS (protein inhibitor of activated STAT) proteins form a conserved family defined by an unusual RING-related motif. Our results suggest that this family functions by promoting SUMO conjugation to specific substrates.