In recent years, the field of proteolysis has experienced a surge in interest and notable achievements, which has led to a growing number of conferences, reviews, and publications centered around this topic. Biochimie has been a pioneer in promoting this progress. Since 2008, the journal has published four thematic issues devoted to the ever-evolving field of proteolytic enzymes: “Cellular proteolysis” (Vol. 90(2), February 2008), “Protease inhibitors and biological control” (Vol. 92(11), November 2010), “A potpourri of proteases and inhibitors: from molecular toolboxes to signaling scissors” (Vol. 122(C), March 2016) and “Proteases: goldies enzymes always on the agenda” (Vol. 166, November 2019). All issues received an extremely positive welcome, which materialized by both number of readings and rate of citations and quotations. Given these previous positive achievements, we are pleased to have accepted the role of Guest Editors for a fifth thematic issue of Biochimie entitled “At the crossroads of proteostasis and proteolysis”. In this special issue, we have curated a collection of articles that we hope will be both insightful and engaging. We extend our sincere thanks to Prof. Bertrand Friguet, Editor-in-Chief of Biochimie, for his invaluable role as the handling editor in managing the manuscripts for this issue. But why this title “At the crossroads of proteostasis and proteolysis»? The adventure was inspired by the successful organization of a recent scientific joint conference between the “cellular proteolysis” thematic group of the French Society of Biochemistry and Molecular Biology (SFBBM) and one of the four working groups of the COST European network “ProteoCure” (so called “a sound proteome for a sound body: targeting proteolysis for proteome remodeling”). This conference (https://proteolysis2023.sciencesconf.org/), held in the beautiful and historical Campus Les Cordeliers-Sorbonne Université (May 22–24th, 2023, Paris, France), was co-organized by Chahrazade El Amri and Bertrand Friguet (Sorbonne Université, CNRS, INSERM, Paris, France), Carmela Giglione (Université Paris-Saclay, CEA, CNRS, Gif-sur-Yvette, France), and Gilles Lalmanach (Université de Tours, INSERM, Tours, France). It brought together more than a hundred people from 15 countries (mainly European as well as a large delegation from South Korea). Organized into six main sessions (Inflammation, Cancer, Autophagy, Omics and Drug Design, Host-Pathogens Interactions, Aging and Neurodegenerative Diseases), the conference was a tremendous success. It fostered rich scientific discussions among attendees, complemented by friendly social interactions, particularly during the enjoyable wine and cheese gatherings that further enhanced the collaborative atmosphere.