Recent decades have witnessed a distinct worldwide trend of launching national programs and projects to develop and expand a group of the so-called “world-class” universities with the aim of enhancing the quality and prestige of respective national systems of higher education. This article presents a case study that matches the results of 5–100 Project, an ambitious university excellence initiative in Russia (terminated in December 2020) against the originally set targets and criteria of success. In addition, the key elements of the project are compared to similar programs in other countries (e.g., the German Universities Excellence Initiative – Exzellenzinitiative). The following research questions determine the focus of the research efforts: (1) “What are the challenges in introducing university excellence programs in Russia and other countries? (2) What are the weaknesses of the program design and implementation? and 3) What strategy would likely ensure effective achievement of the program objectives?” Data are derived from published and unpublished materials, archival records, and interviews. Though primarily a comparative case study, this article offers implicit and explicit contributions to knowledge and literature on higher education systems worldwide. Institutional theory and resource dependence theory as well as political economy of “marketization” help frame a theoretical grounding for this primarily case study article. The undertaken study also seeks to contribute to the identification of key nationally and globally tied factors that define favorable conditions for enhancing excellence of higher educational institutions with measurable outcomes. It further outlines two major areas for further research on the subject.