Cancer chemoprevention approaches generally use long-term, continuous treatment, which can produce major preventive effects but which can also have unexpected serious adverse events. This raises the question of whether intermittent dosing schedules might reduce toxicity while retaining benefit, a concept that we call short-term intermittent therapy to eliminate premalignancy (SITEP). Recent preclinical studies support a novel SITEP approach whereby short-term, intermittent therapy eliminates premalignant cells via apoptosis that is induced by synthetic lethal interactions. Synthetic lethality allows personalized, selective elimination of premalignant clones without harming normal cells. This Opinion article provides a detailed discussion of the principle, method and future development of the SITEP approach.