Due to their early origin and extreme conservation, cofactors are valuable molecular fossils for tracing the origin and evolution of proteins. First, as the order of protein folds binding with cofactors roughly coincides with protein‐fold chronology, cofactors are considered to have facilitated the origin of primitive proteins by selecting them from pools of random amino acid sequences. Second, in the subsequent evolution of proteins, cofactors still played an important role. More interestingly, as metallic cofactors evolved with geochemical variations, some geochemical events left imprints in the chronology of protein architecture; this provides further evidence supporting the coevolution of biochemistry and geochemistry. In this paper, we attempt to review the molecular fossils used in tracing the origin and evolution of proteins, with a special focus on cofactors. Mutual support: Cofactors play important roles in the origin and evolution of proteins. Nucleotide‐containing cofactors might have facilitated the origin of primitive proteins by selecting them from random amino acid sequences. Metallic cofactors also link protein evolution with geochemical variations; this provides further evidence supporting the coevolution of biochemistry and geochemistry.