One of the main challenges in modern medicinal chemistry is designing new molecular structures that fulfil desired design objectives. However, the space of all possible molecular structures that could be feasibly synthesised has been estimated to be upwards of 10⁶⁰. This value is not only truly astronomical, but there are fewer atoms in the universe than would be necessary to realise all of the structures. This chapter covers the theory and methods by which molecular structures are sampled from the theoretical chemical space and how the candidate solutions are evaluated. Some successful examples of de novo design applications in recent challenges in drug design are outlined. Lastly, the outlook for the future will be given, including the potential for a closed-loop system for design, synthesis, testing and subsequent analysis to be developed in the near future.