Citation Giants: How the Most-Cited Papers of the 21st Century Are Reshaping Science

The scholarly landscape has witnessed a dramatic transformation in the first quarter of the 21st century. While groundbreaking discoveries like mRNA vaccines, CRISPR gene editing, the Higgs boson, and gravitational wave detection dominate headlines, they surprisingly don’t appear among the most-cited papers published since 2000. Instead, the citation champions represent the essential infrastructure of modern science: artificial intelligence architectures, research methodologies, statistical software, and clinical data that enable countless other discoveries.

Microsoft’s 2016 paper on deep residual learning networks (ResNets) claims the crown as the century’s most-cited work, accumulating over 254,000 citations according to Google Scholar. This paper solved a fundamental problem in neural network training—signal degradation through many layers—enabling networks with 150 layers compared to the previous standard of 30. The ResNet architecture became foundational for AI breakthroughs from AlphaGo’s game mastery to AlphaFold’s protein structure predictions and ultimately ChatGPT’s language modeling capabilities.

The COVID-19 pandemic accelerated citation patterns in unprecedented ways. Guan Wei-jie’s clinical characterization of coronavirus disease garnered over 16,000 citations within just three years, demonstrating how urgent global health crises can rapidly elevate research visibility. Machine learning applications for COVID-19 diagnosis, drug discovery, and epidemiological modeling became citation magnets as researchers worldwide sought computational solutions to pandemic challenges.

Cancer research maintains its position as a citation powerhouse through foundational works that continue accumulating references decades after publication. Douglas Hanahan’s “Hallmarks of Cancer” framework and WHO’s GLOBOCAN cancer statistics serve as essential starting points for virtually every cancer study, while emerging CRISPR-based therapeutics represent the field’s future direction.

Perhaps most tellingly, research software and methodological papers dominate the citation landscape. George Sheldrick’s SHELX crystallography software, Virginia Braun and Victoria Clarke’s thematic analysis methodology, and various bioinformatics tools like DESeq2 demonstrate how methodological innovations become the workhorses of scientific progress. These papers succeed not through revolutionary discoveries but by providing reliable, accessible tools that thousands of researchers depend upon.

The concentration of highly cited papers in artificial intelligence, computational biology, and research methodology reveals a profound shift toward interdisciplinary, data-driven science. Today’s most influential research doesn’t just make discoveries—it creates the computational and analytical foundations that enable entire fields to advance. This pattern suggests that 21st-century science increasingly values infrastructure over individual breakthroughs, with the most cited papers serving as the digital scaffolding supporting the modern research enterprise.