Although sharing a common conjugation pathway, SUMO1, SUMO2/3 and SUMO4 seem to play preferential roles in the cell. Recently, many regulatory mechanisms contributing to SUMO paralogs specific modification have emerged. SUMO enzymes can discriminate between SUMO paralogs at both conjugation and deconjugation levels. Moreover, many substrates possess characteristics that promote their preference for different SUMO family members. A better knowledge of the mechanisms promoting SUMO specific modification will improve our understanding of the functions of SUMO paralogs in distinct cellular pathways.