Initially the concern on scale-up of fermentation processes was with oxygen transfer. Strain stability on scale-up was thought to be sufficiently established by serial transfer in shake flasks where conditions were homogeneous. Unfortunately, we now know that there are often mixing problems in large-scale fermenters. The conditions within the vessel can be highly non-homogeneous even-on a macro-scale. These nonhomogeneous variations include temperature, dissolved oxygen, and fluid shear. Such variations can cause strain degredation and failure of a strain to perform satisfactorily over long fermentation times in large-scale vessels. Also, the highly mutated industrial strains often have hidden auxotrophy that only may be exposed in non-homogeneous conditions. For this reason scale-up is still an art not an exact science. We need to learn how to achieve better mixing in large-scale fermenters.