A linear theory of the generalized Rayleigh-Taylor instability (GRTI) is derived which includes ion inertia and acceleration forces, as well as E region drivers: the zonal neutral wind and plasma drift. This is in contrast to the F region drivers aside from gravity: the meridional neutral wind and the meridional/vertical plasma drifts. Both a local theory and a flux-tube integrated theory are presented with application to the onset of ionosphere irregularities associated with equatorial spread F. Inertia and acceleration forces do not affect the growth rate of the GRTI for nominal ionospheric conditions, but the E region zonal drifts can significantly increase or decrease the growth rate of the GRTI in the equatorial and mid-latitude ionosphere depending on their direction.