Objective: Knowledge of the procedural requirements for international research is not widely disseminated to investigators involved in the administration of a federal grant with a foreign component. The purpose of this article is to highlight the major challenges in administrative, procedural, and equipment management aspects of grant implementation when federal funding is involved in international collaborative research. Methods: The author describes the procedural requirements for international research from the time of priority score receipt to the implementation of the grant. Results: There is tremendous promise for rewarding experiences in international research projects due to the collaboration, mutual learning, and cultural bridging that intrinsically occur. However, there are also inherent cross-national procedural requirements that can be demanding in time and effort for the investigator and other stakeholders of the grant. Conclusions: It is hoped that awareness of these difficulties and demystification of the process for future investigators can minimize the potential encumbrances in such international research.