Computational and mathematical models are key to obtain a system-level understanding of biological processes, but their limitations have to be clearly defined to allow their proper application and interpretation. Crowdsourced benchmarks in the form of challenges provide an unbiased assessment of methods, and for the past decade, the Dialogue for Reverse Engineering Assessment and Methods (DREAM) organized more than 15 systems biology challenges. From transcription factor binding to dynamical network models, from signaling networks to gene regulation, from whole-cell models to cell-lineage reconstruction, and from single-cell positioning in a tissue to drug combinations and cell survival, the breadth is broad. To celebrate the 5-year anniversary of Cell Systems, we review the genesis of these systems biology challenges and discuss how interlocking the forward- and reverse-modeling paradigms allows to push the rim of systems biology. This approach will persist for systems levels approaches in biology and medicine.