The major aims of biology to understanding life at a systems level. Escherichia coli is a metabolically versatile bacterium able to respond to changes in environmental factors availability. The effect of pH downshift on fermentation characteristics was investigated in a continuous culture of Escherichia coli at aerobic and micro-aerobic conditions. Regardless of oxygen availability, higher levels of acetate were associated with lower biomass yields and lower glucose consumption rates at pH 5.5 as compared to the observations made at pH 7.0. Observed gene expressions indicated that the down- regulation of the glucose uptake rate corresponded to the down-regulation of ptsG gene expression which in turn was caused by the up-regulation of mlc gene under the positive control of Crp. In accordance with up-regulation of arcA gene expression at acidic conditions, the expressions of TCA cycle-related genes such as icdA and gltA, and the respiratory chain gene cyoA were down-regulated, whereas cydB gene expression was up-regulated. Decreased activity of the TCA cycle caused more acetate formation at lower pH levels. Under micro-aerobic condition, higher levels of formate and lactate were produced at lower pH due to up-regulation of pflA, yfiD and ldhA genes. Meanwhile, lower levels of ethanol were produced due to the down-regulation of adhE gene at lower pH, as compared to the observation at neutral pH. The combined effect of pH and temperature on gene expression was also investigated and observed that decreases in the specific glucose consumption rate were associated with increases in the specific acetate production rate. This type of information is useful for the production of recombinant proteins, bio-molecules, simultaneous saccharification and fermentation (SSF) and strain improvement.