Ball milling is one of the most common unit operations used for size reduction across a range of industries. However, it is also a notoriously inefficient process, often contributing substantially to operational costs. In this work, we investigate the influence of rotation rate, grinding media fill level and grinding media size on the optimal production of a product of intermediate size. We find that changing the grinding media size at otherwise identical conditions produces different breakage products as well as nonmonotonic trends with varying rotation rate and grinding media fill levels. In addition, we show how to use the attainable region analysis to explore the parameter space in a reduced time without having to perform tests at every parameter combination. Finally, we examine how the complex interplay between rotation rate, grinding media fill level and grinding media size can control the mechanism of breakage occurring inside a ball mill. (c) 2011 American Institute of Chemical Engineers AIChE J, 2012