If methane, the main component of natural gas, can be efficiently converted to liquid fuels, world reserves of methane could satisfy the demand for transportation fuels in addition to use in other sectors. However, the direct activation of strong C-H bonds in methane and conversion to desired products remains a difficult technological challenge. This perspective reveals an opportunity to rethink the logic of biological methane activation and conversion to liquid fuels. We formulate a vision for a new foundation for methane bioconversion and suggest paths to develop technologies for the production of liquid transportation fuels from methane at high carbon yield and high energy efficiency and with low CO₂ emissions. These technologies could support natural gas bioconversion facilities with a low capital cost and at small scales, which in turn could monetize the use of natural gas resources that are frequently flared, vented or emitted.