Mitogen-activated protein kinase (MAPK) cascades are conserved signaling pathways that transduce extracellular signals into diverse cellular responses. Arabidopsis MAPKKK18 is a component of the MAPKKK17/18-MKK3-MPK1/2/7/14 cascades, which play critical roles in abscisic acid (ABA) signaling, drought tolerance and senescence. A very important aspect of MAP kinase signaling is both its activation and its termination, which must be tightly controlled to achieve appropriate biological responses. Recently, the ubiquitin-proteasome system (UPS) has received increasing attention as a key mechanism for maintaining the homeostasis of MAPK cascade components and other ABA signaling effectors. Previous studies have shown that the stability of MAPKKK18 is regulated by the UPS via the ABA core pathway. Here, using multiple proteomic approaches, we found that MAPKKK17/18 turnover is tightly controlled by three E3 ligases, UPL1, UPL4 and KEG. We also identified lysines 154 and 237 as critical for MAPKKK18 stability. Taken together, this study sheds new light on the mechanism that controls MAPKKK17/18 activity and function.