Determining whether the molecular target is a good candidate for evaluation in a Phase 0 clinical trial. The decision to proceed with a Phase 0 rather than Phase I trial to evaluate a drug’s effect on its molecular target depends both on the amount of variability in the target and the therapeutic index of the targeted agent. Sampling variability in the pharmacodynamic endpoint due to tumor heterogeneity, diurnal variation, or other factors can be “low” or “high” for a baseline evaluation. Molecular targets suitable for Phase 0 trials can have either low (A) or high (B) variability at baseline, as long as there is a non-toxic dose of the investigational agent that achieves a degree of target modulation that lies outside the baseline range. Targets are not suitable for Phase 0 trials (C) if target modulation by the investigational drug is never significantly different from baseline, or (D) if a significant difference in target activity can be achieved only at potentially toxic drug doses. In both (C) and (D), the targets would be better approached with a traditional Phase I trial in which the drug dose can be escalated to determine dose limiting toxicity.