"Evolution consists largely of molecular tinkering."-Following the famous concept of the molecular geneticist and medicine Nobel laureate François Jacob, in this review we describe the structural evolution of dopamine D3 receptor ligands from the natural agonist dopamine (DA) to highly potent and subtype selective new agents by bioisosteric tinkering with well-established and privileged or novel and fancy chemical functionalities and scaffolds. Some of the more than 200 ligands presented herein have already achieved therapeutic or scientific value up to now, some will most likely achieve it in the future. Hence, great importance is not only attached to the relationship between structure and activity of the ligands, but also to their utility as pharmacological tools in animal models or as therapeutics in patients with neurological diseases or other disorders.