Gastrointestinal and liver cancers are among the most frequently encountered cancers worldwide. Though great strides have been made in improving the early detection and overall patient survival in the last decade, the currently available treatment approaches remain suboptimal due to drug resistance and side effects. Apoptosis is the most desirable type of programmed cell death in cancer therapy. By eliminating unnecessary and unwanted cells, apoptosis plays a critical role in development, physiology and homeostasis. Recent studies have shown that apoptosis-inducing therapy is a safe and effective anti-cancer approach, which thus may become one of the most important areas in cancer treatment. In this review, the authors provide an overview on the apoptosis system in multicellular organisms and summarize the recent advances of apoptosis-inducing therapeutic strategy for gastrointestinal and liver cancers.