The possible permutations of small molecules, gene and protein sequences that could have participated in the origins of living systems, and the further permutations of their possible interactions are astronomical. Living systems utilize only a tiny fraction of these to form modern interactomes. How, in the face of extraordinary permutational possibilities, did these interactomes evolve, and how do they retain their integrated functions against persistent and ongoing mutational variation? This chapter focuses on a particular aspect of this larger problem, which is how the receptor and transporter systems essential to cellular life evolved. Did receptors and transporters evolve independently of their ligands, in which case, how did they become integrated and functional? If receptor– or transporter–ligand pairs coevolved by selection for specific functions, by what process? This chapter argues the process that limits permutational possibilities, creates interactomes, and endows them with functions involves a combination of two mechanisms: 1) modularity, using small, repeating units of structure to build more complex molecules; and 2) selection for molecular complementarity, non-covalent interactions among molecules mediated by stereochemical fit. The molecular paleontology inherent in modern interactomes demonstrates selection for molecularly complementary modules (MCMs). Two case studies explore how MCM was used to bootstrap complex systems from small-molecule complexes: the evolution of (1) glucose regulation and (2) adrenergic and opioid receptor–ligand pairs and their cross talk.