This review paper describes systems used to cultivate microalgae for biofuel production. It addresses general design considerations pertaining to reactors that use natural light and photosynthetic growth mechanisms, with an emphasis on large-scale reactors. Important design aspects include lighting, mixing, water consumption, CO2 consumption, O-2 removal, nutrient supply, temperature, and pH. Though open pond reactors are the most affordable option, they provide insufficient control of nearly all growth conditions. In contrast, a variety of closed reactors offer substantial control, but few feature the likelihood for levels of productivity that offset their high cost. One of the greatest challenges of closed photobioreactor design is how to increase reactor size in order to benefit from economy of scale and produce meaningful quantities of biofuel. This paper also highlights the concept of combining open and closed systems and concludes with a discussion regarding a possible optimal reactor configuration.