Targeting synthetic lethal interactions between genes has emerged as a promising strategy for cancer therapy. This study explores the intricate interplay between terminal uridyltransferase 4 (TUT4) and terminal uridyltransferase 7 (TUT7), the 3'-5' exoribonuclease DIS3L2, and the SKI complex-interacting factor Focadhesin (FOCAD) in the context of cancer vulnerability. Using CRISPR and public functional genomics data, we show impairment of cell proliferation upon knockout of TUT7 or DIS3L2, but not TUT4, on cancer cells with FOCAD loss. Moreover, we report the characterization of the first potent and selective TUT4/7 inhibitors that substantially reduce uridylation and demonstrate in vitro and in vivo antiproliferative activity specifically in FOCAD-deleted cancer. FOCAD deficiency post-transcriptionally disrupts the stability of the SKI complex, whose role is to safeguard cells against aberrant RNA. Re-introduction of FOCAD restores the SKI complex and makes these cells less sensitive to TUT4/7 inhibitors, indicating that TUT7 dependency is FOCAD loss-driven. We propose a model where, in absence of FOCAD, TUT7 and DIS3L2 function as a salvage mechanism that degrades aberrant RNA, and genetic or pharmacological inhibition of this pathway leads to cell death. Our findings underscore the significance of FOCAD loss as a genetic driver of TUT7 vulnerability and provide insights into the potential utility of TUT4/7 inhibitors for cancer treatment.