Nuclear medicine technologists and investigators who perform imaging procedures in clinical trials often have not received training on clinical research regulations, such as Title 21, part 312, of the Code of Federal Regulations or Good Clinical Practices. These regulations directly affect implementation of the therapeutic or imaging protocol. Lack of understanding of the regulatory expectations in clinical research can lead to unintended errors or omissions in critical data that are needed for development of a new drug. One common error is not following the protocol exactly as written, or modifying the imaging parameters in some way as to make the data nonstandard from site to site. These errors and omissions are a source of delay in the development of new imaging and therapeutic products. Although not following the protocol does not result in criminal penalties per se, errors and omissions can lead to regulatory consequences such as warning letters to the investigator or sponsor, which if not resolved can lead to barring a site or investigator from participation in any future research trials. Pharmaceutical sponsors, device sponsors, and federal granting agencies such as the National Cancer Institute enter into contracts with imaging sites under the expectation that the investigator and all research staff know and understand clinical research regulations. This article is intended to teach imaging personnel what any sponsor (pharmaceutical, device, or federal agency) is expecting from research imaging and how lack of understanding of Good Clinical Practices and federal regulations can impede the optimal success of a research study. After reading this article, nuclear medicine technologists should be able to understand the importance of following the clinical trial protocol to exact specifications, create a list of questions that should be answered by the sponsor or trial organizers before patient enrollment, describe Form FDA 1572, and describe the terms protocol, protocol deviation, protocol violation, and protocol exception.