The chapter discusses the enhancement of protein crystal nucleation through critical density fluctuations. Numerical simulations of homogeneous crystal nucleation for a model globular protein show that the presence of a metastable fluid-fluid critical point significantly reduces the free-energy barrier for crystal nucleation, leading to a substantial increase in the nucleation rate. This critical point can be controlled by adjusting the solvent composition, providing a systematic approach to promote protein crystallization. The simulations reveal that near the critical temperature, the nucleation barrier is much lower, and the wetting of the crystal nucleus by a liquidlike layer results in a lower interfacial free energy, reducing the barrier height. This finding suggests that adjusting solvent conditions to locate the metastable fluid-fluid critical point just below the sublimation curve can selectively speed up crystal nucleation without increasing crystal growth or amorphous aggregate formation. The mechanism described is likely general for compact macromolecules and could be used to facilitate the formation of ordered structures in nature.The chapter discusses the enhancement of protein crystal nucleation through critical density fluctuations. Numerical simulations of homogeneous crystal nucleation for a model globular protein show that the presence of a metastable fluid-fluid critical point significantly reduces the free-energy barrier for crystal nucleation, leading to a substantial increase in the nucleation rate. This critical point can be controlled by adjusting the solvent composition, providing a systematic approach to promote protein crystallization. The simulations reveal that near the critical temperature, the nucleation barrier is much lower, and the wetting of the crystal nucleus by a liquidlike layer results in a lower interfacial free energy, reducing the barrier height. This finding suggests that adjusting solvent conditions to locate the metastable fluid-fluid critical point just below the sublimation curve can selectively speed up crystal nucleation without increasing crystal growth or amorphous aggregate formation. The mechanism described is likely general for compact macromolecules and could be used to facilitate the formation of ordered structures in nature.