For nearly 50 years, scientists have struggled to solve one of nature’s most perplexing challenges--predicting the complex 3D shape a string of amino acids will fold into as it becomes a working protein. This year, scientists have shown that artificial intelligence (AI)-driven software can achieve this long-standing goal and predict accurate protein structures by the thousands. To honor this feat, on December 17, 2021, Science named AI-powered protein prediction as its 2021 Breakthrough of the Year. “This is a breakthrough on two fronts,” writes Science Editor-in-Chief Holden Thorp, PhD, in a related Editorial. “First, it solves a scientific problem that has been on the to-do list for 50 years… Second, it’s a game-changing technique that, like CRISPR or cryo-EM, will greatly accelerate scientific discovery.”