RNA interference (RNAi) is an epigenetic mechanism involved in regulation of gene expression. It relies on small non-coding RNAs: endogenous miRNA and exogenous siRNA. Among various vital processes in the cell, RNAi regulates the cell cycle progression and apoptosis. Hence, (epi)mutations of the RNAi system can force the cell toward promotion of proliferation and evasion of apoptosis leading to neoplastic transformation. Aberrant RNAi is commonly found in various cancers or even precancerous lesions and seems to be involved in anti-cancer drug resistance as well. Therefore biomedical science nowadays tends to identify RNAi profiles and translate them into clinical biomarkers for cancer diagnostics and therapy response. Since exogenous branch of RNAi pathway sustains specific iatrogenic regulation of gene expression, intense attempts of developing novel anticancer therapy approaches using synthetic small non-coding RNAs are on-going. Several experimental RNAi therapies in different stages of clinical trials are expected to inhibit cell proliferation and re- establish apoptotic activity in transformed cells. In this review we focus on recent discoveries of RNAi regulating apoptosis, enclose these findings in cancer biology context and discuss potential translation of the field into clinical medical practice considering novel trends in management of cancer.