This chapter presents a historical overview and contemporary insights into the crystallisation of biological macromolecules. It looks at what knowledge has been obtained about the crystallisation of small molecules and how it relates to biomolecules. While the principles of supersaturation and nucleation are the same for both, the complexity of biomolecules presents unique challenges to their crystallisation. Before crystallisation experiments begin with the biomolecule, it is advisable to assay the purity, measure the concentration, and choose a suitable solvent formulation. These parameters are not necessarily straightforward to evaluate. Thereafter, the initial crystallisation screening attempts to examine the effects of chemical space, temperature, pH, and kinetics. Because initial screens do not typically produce diffraction-quality crystals, suggestions are offered for how to optimise screening outcomes. In this context, seeding is particularly powerful, on its own, or in synergy with other optimisation techniques. The chapter concludes with the observation that biomolecular crystallisation remains a poorly understood problem. It is proposed that collecting more information about the crystallisation experiments – both the failed and successful ones – may contribute to a better understanding of the process.