Many different PBR designs have been proposed for biofuel production, few of them have been tested at pilot-scale, none developed at the (large) scale necessary for a complete and correct evaluation. Thus the main issues that impact on the reactor's performance (i.e., suitable construction materials, efficient mixing, heating/cooling, CO2 supply and oxygen removal), although explored at pilot level, still await evaluation at real scale. Although the main limitations of PBR are the high cost and the reduced scalability, with few exceptions, R&D on photobioreactor design is aimed at achieving high photosynthetic efficiencies and at pushing productivity beyond that currently attainable. The main strategies explored to this end are intensive mixing, light dilution via large external surfaces or internal light conducting structures. This chapter reviews and examines recent advances and innovations in photobioreactor design and operation.