Large-scale production of microalgae for biofuels is still facing several major challenges to become competitive with other forms of renewable and nonrenewable energy. A major challenge is harvesting, which requires the separation of a low amount of biomass consisting of small individual cells from a large volume of culture medium. Flocculation is seen as a promising low-cost harvesting method for microalgae biomass. In this chapter, the challenges and potential advantages of using flocculation as a harvesting method for microalgae are reviewed.