Protein synthesis plays an important role in the regulation of cell proliferation. While the role of cap-dependent translation in cell transformation has been studied extensively another translation initiation mechanism, internal initiation of cellular mRNAs, emerged recently and is relatively unappreciated and poorly understood. Internal initiation is mediated by IRES elements that are found in the 5 untranslated region (5 UTR) of mRNA. Curiously, several oncogenes, growth factors and proteins involved in the regulation of programmed cell death contain IRES elements in their 5 UTRs. Internal initiation escapes many control mechanisms that regulate cap-dependent translation. In this review I will discuss the data supporting the hypothesis that selective translation of these factors may contribute to the survival of cancer cells under stressful situations, such as lack of nutrients, hypoxia, or therapy-induced DNA damage and contributes to the development and progression of cancer and to the establishment of cancer cells that are resistant to conventional therapies.