Ribozymes have progressed from an intriguing subject of scientific study to therapeutic agents for the potential treatment of a fatal and devastating viral infection. Despite this rapid road to clinical trials, there are many unexplored avenues that should be examined to improve the intracellular effectiveness of ribozymes. Since ribozymes are RNA molecules, the cellular rules governing RNA partitioning and stability can be applied to these molecules to make them more effective therapeutic agents. Future, successful therapeutic ribozyme applications will depend upon increasing our knowledge of RNA metabolism and movement, and applying this knowledge to the design of ribozymes. This chapter discusses experimental approaches towards this goal as well as recent progress in the application of a pair of hammerhead ribozymes for the clinical treatment of HIV1 infection.