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Due to their capability to transport chemicals or proteins into target cells, cell‐penetrating peptides (CPPs) are being developed as therapy delivery tools. However, and despite their interesting properties, arginine‐rich CPPs often show toxicity for reasons that remain poorly understood. Using a (PR)n dipeptide repeat that has been linked to amyotrophic lateral sclerosis (ALS) as a model of an arginine‐rich CPP, we here show that the presence of (PR)n leads to a generalized displacement of RNA‐ and DNA‐binding proteins from chromatin and mRNA. Accordingly, any reaction involving nucleic acids, such as RNA transcription, translation, splicing and degradation, or DNA replication and repair, is impaired by the presence of the CPPs. Interestingly, the effects of (PR)n are fully mimicked by protamine, a small arginine‐rich protein that displaces histones from chromatin during spermatogenesis. We propose that …