Biogas production requires a number of different microbial groups that work in a synchronized and closely interacting manner. For bioreactors constructed to maximize waste treatment and energy production, it is crucial to manage this process in a way that secures the growth and activity of these microorganisms, as otherwise there is a great risk of process failure. However, the microbiome has a remarkable ability to adapt to various conditions related to substrate composition and operating conditions, thus showing high functional redundancy and robustness. In order to optimize and steer the process, it is important to have an understanding of the anaerobic microbiome, how it responds to various conditions, and its upper limits. This chapter reviews current knowledge regarding microbial responses to different operational management strategies. Microbial responses under various conditions and how the process can be operated to maintain the activity of key species are addressed. Parameters discussed include for example substrate composition, pretreatment, ammonia level, temperature and organic load.