Electro-osmotic flow is a convenient mechanism for transporting fluid in microfluidic devices. The flow is generated through the application of an external electric field that acts on the free charges that exist in a thin Debye layer at the channel walls. The charge on the wall is due to the particular chemistry of the solid–fluid interface and can vary along the channel either by design or because of various unavoidable inhomogeneities of the wall material or because of contamination of the wall by chemicals contained in the fluid stream. The channel cross-section could also vary in shape and area. The effect of such variability on the flow through microfluidic channels is of interest in the design of devices that use electro-osmotic flow. The problem of electro-osmotic flow in a straight microfluidic channel of arbitrary cross-sectional geometry and distribution of wall charge is solved in the lubrication approximation, which is justified when the characteristic length scales for axial variation of the wall charge and cross-section are both large compared to a characteristic width of the channel. It is thereby shown that the volume flux of fluid through such a microchannel is a linear function of the applied pressure drop and electric potential drop across it, the coefficients of which may be calculated explicitly in terms of the geometry and charge distribution on the wall. These coefficients characterize the ‘fluidic resistance’ of each segment of a microfluidic network in analogy to the electrical ‘resistance’ in a microelectronic circuit. A consequence of the axial variation in channel properties is the appearance of an induced pressure gradient and an associated secondary flow that leads to increased Taylor dispersion limiting the resolution of electrophoretic separations. The lubrication theory presented here offers a simple way of calculating the distortion of the flow profile in general geometries and could be useful in studies of dispersion induced by inhomogeneities in microfluidic channels.