In order to determine the applicability of noninvasive magnetic resonance spectroscopy (MRS) to the study of a diseased tissue or organ in the human body, it is necessary to determine if MRS is safe and effective. This is the primary purpose of a clinical trial. A clinical trial for MRS may also reveal which technical approach works best for the specific application and characteristics of the population being studied. In this chapter, we discuss the legal, ethical, and scientific requirements to be considered prior to the start of a clinical trial of an MRS protocol, as well as constraints that may arise during its execution. MRS-specific issues arising from a couple of successful clinical MRS trials for classifying brain tumors with 1H MRS (INTERPRET and eTUMOUR) and body tumors with 31P MRS (the Cooperative Group on MRS Application in Cancer, CoGMAC), serve as illustrative examples.