A new generalized high-frequency transmission line model is presented for general uniform hybrid waveguide structures consisting of inhomogeneous isotropic or anisotropic media. Starting from Maxwell’s equations, the generalized coupled telegrapher’s equations are found and the frequency-dependent transmission line parameter matrices R(ω), G(ω), L(ω), and C(ω) are defined in an unambiguous way as integral expressions of the normalized electromagnetic fields over the cross section of the structure. Some examples illustrate this general circuit-oriented modeling approach. In the appendix we also present a new extended high-frequency circuit model for general uniform hybrid waveguide structures consisting of chiral anisotropic inhomogeneous media.