Artificial macrocycles recently became popular as a novel research field in drug discovery. As opposed to their natural twins, artificial macrocycles promise to have better control on synthesizability and control over their physicochemical properties resulting in druglike properties. Very few synthetic methods allow for the convergent, fast but diverse access to large macrocycles chemical space. One synthetic technology to access artificial macrocycles with potential biological activity, multicomponent reactions, is reviewed here, with a focus on our own work. We believe that synthetic chemists have to acquaint themselves more with structure and activity to leverage the design aspect of their daily work.1 Introduction2 Macrocycle Properties and Receptor Binding3 Synthetic Approaches towards Artificial Macrocycles Using MCR4 Design Rules for Membrane Crossing Macrocycles5 Design Rules for Libraries of Macrocycles6 Computational Macrocyclic Methods7 Future View