Background: Clinical trials are an integral part of translating new basic science research into therapeutics. It is crucial for those who run clinical trials to realize the gravity of their responsibilities as principal investigators.; Methods: This review focuses on the relevant investigator responsibilities under the Code of Federal Regulations Title 21, the contents of Form 1572, FDA inspections, and methods to improve compliance.; Results: While responsibility for day-to-day study activities can be delegated to outside entities and to study staff, a clinical principal investigator who has signed US Food and Drug Administration (FDA) Form 1572 is held responsible for noncompliance and misconduct by anyone working on the study. Depending on the infraction, consequences can range from a publicly posted warning letter by the FDA to criminal prosecution and fines or imprisonment.; Conclusion: Investigators are not only responsible for producing high-quality, meaningful, scientific research, but they are also responsible for maintaining public trust. If the principal investigator acts with integrity and provides training and oversight of employees, FDA inquiries should go smoothly. Following good clinical practice standards for clinical research will result in quality data collection and facilitate the analysis and publication process.