Nature utilizes a diverse set of tetrapyrrole-based macrocycles (referred to as porphyrinoids) for catalyzing various biological processes. Investigation of the differences in electronic structure and reactivity in these reactions have revealed striking differences that lead to diverse reactivity from, apparently, similar looking active sites. Therefore, the role of the different heme cofactors as well as the distal superstructure in the proteins is important to understand. This article summarizes the role of a few synthetic metallo-porphyrinoids towards catalyzing several small molecule activation reactions, such as the ORR, NiRR, CO2RR, etc. The major focus of the article is to enlighten the synthetic routes to the well-decorated active-site mimic in a tailor-made fashion pursuing a retrosynthetic approach, learning from the biosynthesis of the cofactors. Techniques and the role of the second-sphere residues on the reaction rate, selectivity, etc. are incorporated emulating the basic amino acid residues fencing the active sites. These bioinspired mimics play an important role towards understanding the role of the prosthetic groups as well as the basic residues towards any reaction occurring in Nature.