Small-cell lung cancer (SCLC) is an aggressive malignancy that is frequently metastatic at presentation and has a poor prognosis. Although initially sensitive to primary therapy, acquisition of apoptosis resistance is typical, resulting in failure of secondary chemotherapy following relapse. Expression of the antiapoptosis protein Bcl-2 is prevalent in SCLC. The understanding of this oncoprotein's function has increased dramatically over the past decade. In vitro and in vivo evidence supports a role for overexpression of Bcl-2 in SCLC and supports the notion that it is a major factor contributing to apoptosis resistance. Targeting Bcl-2 may provide a novel therapeutic approach to overcoming chemoresistance in SCLC. This article discusses the relevance of Bcl-2 to apoptosis susceptibility in SCLC and its exploitation using gene silencing to improve the clinical outcome in this disease.