In recent years expanding knowledge about basic biology and a detailed understanding of the molecular pathways involved in tumor cell growth and progression have allowed the identification of numerous genes as potential therapeutic targets. Studies in which the expression of these genes was manipulated by antisense strategies have provided clues as to how we can intervene to specifically kill tumor cells or sensitize them to conventional chemical and physical antitumor therapies. Such tumor specificity can only be obtained by exploiting a basic difference between normal and malignant cells. In this context, targeting cytoprotective factors such as telomerase and survivin is particularly attractive because of their almost selective expression in tumor cells and their proven association with disease progression. This chapter summarizes the results obtained with ribozymes and small-interfering RNAs in the functional validation of these two targets in cell cultures and animal tumor models.