Designing antagonists to anti-apoptotic proteins of Bcl-2 family has become an important strategy in cancer chemotherapy. Using experimental techniques and computational methods, a few numbers of lead inhibitors to the antiapoptotic proteins have been reported in the literature and a few of them are under clinical trials. In this review, the lead inhibitors designed using in silico methodologies are exclusively covered, systematically organized and critically evaluated. An orchestrated in silico strategy for screening and identifying efficient antagonists to the anti-apoptotic proteins has also been brought into fore.