A comparison of traditional combination drug development versus combination drug repositioning. In traditional combination drug development, novel agent 1 and novel agent 2 must be developed in parallel as single agents. Each compound requires independent discovery, preclinical characterization, absorption, distribution, metabolism, and excretion profiling, and toxicology testing. Suitable compounds require formulation and manufacturing. Phase 1 clinical testing is performed in parallel for each novel agent. Combination phase 1 clinical trials can only be conducted after each agent is independently tested in its own phase 1 trial. The timeline to complete the combination phase 1 trial is approximately 10 to 18 years. In combination drug repositioning, known drugs that act synergistically are identified and evaluated in preclinical studies. Drugs are then acquired for clinical testing. New formulations and manufacturing may be required. By levering the prior toxicology and pharmacology of the compounds, a phase 1 combination trial can be rapidly initiated. The timeline to complete the combination phase 1 study using this approach is approximately 2 to 8.5 years. Professional illustration by A. Y. Chen.