Oligonucleotide-based drugs are now rapidly establishing themselves as an important tool in both research and treatment of genetic disorders. In the past many problems were encountered in using antisense oligonucleotides. Our expanding knowledge and new oligonucleotide chemistries are giving us the chance to treat serious genetic disorders such as cancer in novel, elegant and effective ways not previously possible. In addition, recent knowledge about RNA interference may add to these new approaches for disease treatment with oligonucleotide-based drugs. In this review we discuss one such novel therapeutic strategy against cancer called allele-specific inhibition (ASI). ASI is an approach where cancer cells are attacked at one of the few widely occurring and consistently weak points: the loss of large segments of DNA. Oligonucleotide-based drugs may provide the required selectivity for this therapeutic approach.