Membrane fouling is a major operational problem that leads to reduced membrane performance and premature replacement of membranes. Bacterial biofilms developed on reverse osmosis membranes can cause severe flux declines during whey processing. Various types of biological, physical, and chemical factors regulate the formation of biofilms. Extracellular polymeric substances produced by constitutive microflora provide an effective barrier for the embedded cells. Cultural and microscopic techniques also revealed the presence of biofilms with attached bacterial cells on membrane surfaces. Presence of biofilms, despite regular cleaning processes, reflects ineffectiveness of cleaning agents. Cleaning efficiency depends upon factors such as pH of the cleaning agent, temperature, pressure, cleaning agent dose, optimum cleaning time, and cross-flow velocity during cleaning. Among different cleaning agents, surfactants help to prevent bacterial attachment to surfaces by reducing the surface tension of water and interfacial tension between the layers. Enzymes mixed with surfactants and chelating agents can be used to penetrate the biofilm matrix formed by microbes. Recent studies have shown the role of quorum-sensing-based cell-to-cell signaling, which provides communication within bacterial cells to form a mature biofilm, and also the role of applying quorum inhibitors to prevent biofilm formation. Major cleaning applications are also summarized in Table 1.