Background: Antisense and other RNA-targeting strategies have the potential to impact a broad array of human diseases. Although the methodological approaches for achieving targeted RNA degradation have changed over the past 5 – 10 years, the technological hurdles facing these and other nucleic acid-based drugs have remained fairly constant. Objective: To provide an update on the clinical status of several antisense compounds and discuss methodological strategies for improving efficacy of antisense compounds and other nucleic acid therapeutics. Method: Some of the clinical advances in antisense therapeutics, including a description of sugar or backbone modifications and delivery approaches for improving antisense efficacy are highlighted; a few alternative nucleic acid strategies are discussed. Conclusion: Although a variety of technological issues continue to hamper antisense progress towards the clinic, advances in stabilization and delivery have provided new hope for using nucleic acids as drugs.