Microorganisms in circulating water of power plant bring great harm to cooling water system. It not only affects the effect of heat transfer, but also would lead to corrosion of heat exchanger, in seriously would result in shutdown. Now the plant uses the bactericide to treat with the microbial fouling generally, and a variety of fungicides have been developed. However, the long-term usage of fungicide will make the bacteria appear resistance, which greatly limits the application of such measures. This paper overviewed different resistance mechanisms of Pseudomonas, sulfate-reducing bacteria, iron bacteria and slime forming bacteria in the microbial fouling to bactericide and put forward some solutions.