Over 50 years ago, John Wahren and Lennart Jorfeldt published a manuscript in Clinical Science where they detailed a series of studies of leg blood flow during exercise. They used a novel approach to indicator dye dilution: continuous arterial infusions of dye using venous samples. This technique allowed them to describe for the first time the fundamental relationships between large muscle group exercise, muscle blood flow, and pulmonary and muscle oxygen uptake. They also defined mechanical efficiency, a key measurement of muscle function. This paper formed the basis for research into muscle blood flow and exercise in health and disease and continued to be cited by modern research. In this commentary, we describe the innovations they made, the key observations that came out of their results, and the importance of this manuscript to current research.