Now that guidelines for conducting trials of disease-modifying treatments in systemic sclerosis (SSc) have been published and guidelines for evaluating SSc organ-specific treatments are in preparation, our attention should focus on how to measure disease activity and severity in SSc. Several proposals for measuring disease severity have been forwarded and are discussed. In this editorial, what we know of SSc natural history and pathophysiology is reviewed, and several candidate variables that may reflect disease activity are proposed for evaluation in longitudinal studies and/or drug trials.