Abstract: Oriented-sample NMR (OS NMR) has emerged as a powerful technique for structure determination of membrane proteins in their native lipid environment. In OS NMR, the structural information is directly contained in the spectral positions of the angular-dependent NMR frequencies. Several issues of critical importance for OS NMR are addressed. The first one is sensitivity enhancement by cross-polarization (CP). We propose a new scheme that involves repetitive equilibrations of the proton and nitrogen spin reservoirs between the CP contacts. This provides the transfer of full thermodynamic limit to the low spins, and yields up to 50% signal-to-noise enhancement for biological samples in comparison with the currently used techniques. Second, we have developed a method for spectroscopic assignment of OS NMR spectra using magnetization transfer under the mismatched Hartmann-Hahn conditions. This allows one to transfer magnetization between spins that are over 6 Angstroms apart. The two methods are exemplified by solid-state NMR spectra of a single crystal and Pf1 coat protein reconstituted in magnetically aligned bicelles. Finally, an algorithm that extracts three-dimensional structure entirely from the dipolar couplings is presented. Effect of experimental uncertainty on the quality of the calculated structures is assessed.