Significant progress has been made in the development of ribozymes for a wide variety of intracellular applications, including human gene therapy. Further advances are likely to come from innovative strategies to improve the delivery, expression, co-localization, targeting specificity and substrate turnover of ribozymes. In order to stimulate problem solving in these areas, this article discusses examples of recent successes in intracellular ribozyme applications, and identifies some of the obstacles that remain. In addition, some testable, but as yet untried, ideas for overcoming several of these obstacles are presented.