Biogas production from renewable resources is an alternative to generate energy and concomitantly save fossil fuels and mitigate greenhouse gas emissions. As methanogenesis is a major bottleneck in the biogas process, the determination of the specific activity of methanogenic Archaea can be a good indicator of the process state. A new parameter, the metabolic quotient (MQ), was developed to evaluate the specific activity of methanogens. A standard was created from mesophilic maize-fed fermenters to calculate the expected concentration of methanogens for a given methane productivity at stable process stages. The MQ, the ratio of the predicted to the actual concentration of methanogens, defines their metabolic activity. The MQ was able to indicate methanogenic cell stress metabolism and imminent process failure before conventional chemical parameters. As a further approach, the methanogenic activity was determined by quantification of mRNA transcripts in relation to the mcrA/mrtA-gene, coding for a key enzyme subunit of methanogenesis. The cDNA/DNA ratio reflected the specific actual process activity of the methanogens. As both methods are potent parameters for the early detection of process failure, biogas plant operators may avoid economical losses by their preventive application.