With the increasing number of new drug candidates, the number of those that have poor aqueous solubility is also on the rise. To overcome this limitation, a common formulation approach has been to decrease drug particle size. This strategy results in increased surface area, the potential to increase saturation solubility, and decreased diffusional distance, all of which lead to an increase in the extent and the rate of dissolution. Mechanical techniques to decrease the particle size of solids are generally classified in three categories: dry milling, wet milling, and high-pressure homogenization. In order to produce particles in the submicron (nano) range and further increase solubility, techniques such as wet-media milling, piston-gap homogenization, and microfluidization have been developed. More recently, combination technologies of both top-down and bottom-up approaches have gained much interest. All these different strategies are reviewed and discussed in this updated chapter. This current third edition chapter is a revision and update of the original authors’ work form the first and second editions.