This chapter discusses combination of ultrasound and thermal pre-treatments of waste activated sludge. The sludge flocs were first disintegrated by hydromechanical shear forces created by ultrasonication and then, the increased temperature caused cell lysis by disrupting the chemical bonds in the cell membrane. Long pre-treatment times from several hours to a few days have been reported if thermal pre-treatment was applied alone at temperatures below 100°C. Therefore, ultrasonication has the potential to significantly shorten treatment times when using low-temperature thermal pre-treatment. The sequential application of ultrasonic and thermal pre-treatments is suggested based on the available information on the individual pre-treatments. In addition, if thermal pre-treatment was conducted prior to ultrasonication, significant solids solubilization induced by thermal treatment would leave fewer solids as nuclei for the formation of cavitation bubbles. Heat and ultrasonication can also be used to rupture cells and release the intracellular proteases that can hydrolyze proteins in the sludge.