Escherichia coli remains the best-established production organism in industrial biotechnology. However, when aerobic fermentation runs at high growth rates, considerable amounts of acetate are accumulated as by-product. This by-product has negative effects on growth and protein production. Over the last 20 years, substantial research efforts have been expended on reducing acetate accumulation during aerobic growth of E. coli on glucose. From the onset it was clear that this quest would not be a simple or uncomplicated one. Simple deletion of the acetate pathway reduced the acetate accumulation, but other by-products were formed. This mini review gives a clear outline of these research efforts and their outcome, including bioprocess level approaches and genetic approaches. Recently, the latter seems to have some promising results.