The flexibilization of bioenergy production has the potential to counteract partly other fluctuating renewable energy sources (such as wind and solar power). As a weather-independent energy source, anaerobic digestion (AD) can offer on-demand energy supply through biogas production. Separation of the stages in anaerobic digestion represents a promising strategy for the flexibilization of the fermentative part of biogas production. Segregation in two reactor systems facilitates monitoring and control of the provision of educts to the second methanogenic stage, thus controlling biogas production. Two-stage operation has proven to reach similar or even higher methane yields and biogas purities than single-stage operation in many different fields of application. It furthermore allows methanation of green hydrogen and an easier combination of material and energy use of many biogenic raw and residual biomass sources. A lot of research has been conducted in recent years regarding the process phase separation in multi-stage AD operation, which includes more than two stages. Reliable monitoring tools, coupled with effluent recirculation, bioaugmentation and simulation have the potential to overcome the current drawbacks of a sophisticated and unstable operation. This review aims to summarize recent developments, new perspectives for coupling processes for energy and material use and a system integration of AD for power-to-gas applications. Thereby, cell physiological and engineering aspects as well as the basic economic feasibility are discussed. As conclusion, monitoring and control concepts as well as suitable separation technologies and finally the data basis for techno-economic and ecologic assessments have to be improved.