Several lists of grand challenges in biology have been published recently, highlighting the strong need to answer fundamental questions about how life evolves and is governed, and how to apply this knowledge to solve the pressing problems of our times. To succeed in addressing the challenges of 21st century biology, scientists need to generate, have access to, interpret, and archive more information than ever before. But for many important questions in biology, progress is stymied by a lack of essential tools. Discovering and developing necessary tools requires new technologies, applications of existing technologies, software, model organisms, and social structures. Such new social structures will promote tool building, tool sharing, research collaboration, and interdisciplinary training. Here we identify examples of the some of the most important needs for addressing critical questions in biology and making important advances in the near future.