Decreasing enteric CH4 emissions from ruminants is important for containing global warming to 1.5 °C and avoid the worst consequences of climate change. However, the objective of mitigating enteric CH4 emissions is difficult to reconcile with the forecasted increase in production of ruminant meat and milk, unless CH4 production per animal and per kilogram of animal product are decreased substantially. Chemical compound 3-nitrooxypropanol and bromoform-containing red algae Asparagopsis are currently the most potent inhibitors of rumen methanogenesis, but their average efficacy would have to be increased to mitigate enteric CH4 emissions to contain global warming to 1.5 °C, if the demand for ruminant products increases as predicted. We propose that it may be possible to enhance the efficacy of inhibitors of methanogenesis through understanding the mechanisms that cause variation in their efficacy across studies. We also propose that a more thorough understanding of the effects of inhibiting methanogenesis on rumen and postabsorptive metabolism may help improve feed efficiency and cost-effectiveness as co-benefits of the methanogenesis inhibition intervention. For enhancing efficacy, we examine herein how different inhibitors of methanogenesis affect the composition of the rumen microbial community and discuss some mechanisms that may explain dissimilar sensitivities among methanogens to different types of inhibitors. For improving feed efficiency and cost-effectiveness, we discuss the consequences of inhibiting methanogenesis on rumen fermentation, and how changes in rumen fermentation can in turn affect postabsorptive metabolism and animal performance. The objectives of this review are to identify knowledge gaps of the consequences of inhibiting methanogenesis on rumen microbiology and rumen and postabsorptive metabolism, propose research to address those knowledge gaps and discuss the implications that this research can have for the efficacy and adoption of inhibitors of methanogenesis. Depending on its outcomes, research on the microbiological, biochemical, and metabolic consequences of the inhibition of rumen methanogenesis could help the adoption of feed additives inhibitors of methanogenesis to mitigate enteric CH4 emissions from ruminants to ameliorate climate change.