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What is life? How, where, and when did life arise? These questions have remained most fascinating over the last hundred years. Systems chemistry is the way to go to better understand this problem and to try and answer the unsolved question regarding the origin of Life. Self-organization, thanks to the role of lipid boundaries, made possible the rise of protocells. The role of these boundaries is to separate and co-locate micro-environments, and make them spatially distinct; to protect and keep them at defined concentrations; and to enable a multitude of often competing and interfering biochemical reactions to occur simultaneously. The aim of this Special Issue is to summarize the latest discoveries in the field of the prebiotic chemistry of biomolecules, self-organization, protocells and the origin of life. In recent years, thousands of excellent reviews and articles have appeared in the literature and some breakthroughs have already been achieved. However, a great deal of work remains to be carried out. Beyond the borders of the traditional domains of scientific activity, the multidisciplinary character of the present Special Issue leaves space for anyone to creatively contribute to any aspect of these and related relevant topics. We hope that the presented works will be stimulating for a new generation of scientists that are taking their first steps in this fascinating field.

origin of life --- peptidyl-transferase center --- pseudo-symmetry --- proto-ribosome --- SymR --- emergence of biological systems --- RNA ligation --- dimerization --- standard genetic codes --- codon assignment --- tRNA --- aminoacyl-tRNA synthetase classes --- thiophene --- acetylene --- transition metal sulfides --- hydrothermal conditions --- early metabolism --- origin-of-life --- prebiotic chemistry --- protein–monosaccharide recognition --- protein–monosaccharide interactions --- FRET analysis --- glycocodon theory --- glucose oxidase --- Mars --- prebiotic chemical evolution --- early Earth --- astrobiology --- CHNOPS --- transition elements --- sample return --- exoplanets --- complex organic molecules --- astrochemistry --- interstellar medium --- molecular ices --- solid state --- protoplanetary disks --- star forming regions --- comets --- vesicles --- division --- urea–urease enzymatic reaction --- bending modulus --- budding --- ADE theory --- dynamic kinetic stability --- cognition --- chemical evolution --- systems chemistry --- metabolism --- network expansion simulation --- temperature --- thermodynamics --- protocell --- compartment --- solid interface --- lipid --- polymerization --- cyclic nucleotides --- autocatalytic set --- osmotic pressure --- cell division --- lipid membrane --- bistable reaction system --- template-directed RNA synthesis --- origin of genetic code --- time order of canonical amino acids --- proto-metabolism --- chirogenesis --- quartz --- amino acids --- radiation damage --- GC×GC-TOFMS --- origins of life --- prebiotic membranes --- protoamphiphiles --- metal ions --- hot springs --- N-acyl amino acid --- analogue conditions --- viroids --- ribozyviruses --- primordial replicators --- ribozymes --- bilayer structure --- molecular dynamics --- aggregation process --- selection --- evolution --- Fenton chemistry --- reduced phosphorus --- pyrophosphate --- chemical complexity --- minerals --- schreibersite --- olivine --- serpentinite --- ulexite --- n/a --- protein-monosaccharide recognition --- protein-monosaccharide interactions --- urea-urease enzymatic reaction