Under anoxic conditions in sediments, acetogens are often thought to be outcompeted by microorganisms performing energetically more favorable metabolic pathways, such as sulfate reduction or methanogenesis. Recent evidence from deep subseafloor sediments suggesting acetogenesis in the presence of sulfate reduction and methanogenesis has called this notion into question, however. Here I argue that acetogens can successfully coexist with sulfate reducers and methanogens for multiple reasons. These include (1) substantial energy yields from most acetogenesis reactions across the wide range of conditions encountered in the subseafloor, (2) wide substrate spectra that enable niche differentiation by use of different substrates and/or pooling of energy from a broad range of energy substrates, (3) reduced energetic cost of biosynthesis among acetogens due to use of the reductive acetyl CoA pathway for both energy production and biosynthesis coupled with the ability to use many organic precursors to produce the key intermediate acetyl CoA. This leads to the general conclusion that, beside Gibbs free energy yields, variables such as metabolic strategy and energetic cost of biosynthesis need to be taken into account to understand microbial survival in the energy-depleted deep biosphere.