Cytochrome b(5) (cyt b(5)) is a membrane-anchored electron-carrier protein containing a heme in its soluble domain. It enhances the enzymatic turnover of selected members of the cytochrome P450 superfamily of catabolic enzymes, localized in the endoplasmic reticulum of liver cells. Remarkably, its alpha-helical membrane-anchoring domain is indispensable for the cyt b(5)/cyt P450 interaction. Here, we present the first solid-state NMR studies on holo-cyt b(5) in a membrane environment, namely, macroscopically oriented DMPC:DHPC bicelles. We have presented approaches to selectively investigate different domains of the protein using spectral editing NMR techniques that utilize the unique motional properties of each domain. Two-dimensional H-1-N-15 HIMSELF spectra showed PISA-wheel patterns reporting on the structure and dynamics of the membrane anchor of the protein.