What if proteins that can’t refold in vitro fold perfectly fine inside cells? Our new News & Views article in Molecular Systems Biology, written with Dr. @TrumanLab , explores this interesting insight from Yadav et al. (2025). For decades, chaperone-client relationships have been defined using fundamental in vitro refolding assays, where proteins are unfolded by heat or denaturants and refolded with chaperones. But what happens inside a living cell is far more complex. Using proteome-wide LiP-MS, the authors show that in vivo chaperone requirements don’t necessarily match what refolding assays suggest. Many proteins that fail to refold after denaturation can still fold successfully during co-translational synthesis without the chaperones once thought essential. In our commentary, we discuss how this challenges long-standing assumptions about “chaperone dependence” and highlight the role of the “chaperone code” (post-translational modifications on chaperones) that fine-tunes chaperone functions in the cell. As someone fascinated by how molecular chaperones and their modifications orchestrate proteostasis, I find these findings a powerful reminder of how dynamic folding is within living cells.