The notion of a primitive Earth rich in organic compounds whose accumulation shaped the prebiotic soup is generally accepted. But, did life originate from a vast chemodiversity or rather from a reduced molecular repertoire that anticipated extant biomolecules? Although this issue is not yet solved, prebiotic systems chemistry provides some light on it. This is a new integrative approach based on multicomponent interacting reactions and processes that, unexpectedly, give relatively clean products, instead of intractable mixtures. Christian de Duve proposed that protometabolism was the early chemistry that preceded and prefigured metabolism. Chemical determinism was prominent ab initio, to be later replaced by processes in which evolutionary and historical aspects became increasingly influential. Thus, protometabolism was the necessary chemical setting for the natural selection of “useful” catalytic RNAs (ribozymes) in an RNA world. Evidences of a cyanosulfidic protometabolism, as well as non-enzymatic, geochemical reaction networks reproducing the topology of the metabolic core, support the congruence between protometabolism and metabolism, as suggested by de Duve. Nevertheless, any protometabolic scenario is still far away from what we could recognize as minimal life. This gap should be filled by evolutionary trajectories through transitional systems (protocells) amenable to empirical exploration with bottom-up synthetic biology strategies.