NMR spectroscopy has been widely used to determine high resolution structures of proteins and protein complexes in solution1, 2. However, it is is not suitable for larger proteins (> 30 kDa) due to increased signal decay rates. Deuterium labeling of protein samples overcomes this problem3, but deuteration makes sample preparation much harder and structure determination more difficult4, 5. Here we introduce a strategy that uses non-deuterated samples6. Backbone and side chain resonances of large proteins are assigned from 3D TROSY-HNCA7, 3D MQ-CCH-TOCSY8 and 4D 15N,13C-edited NOESY9 spectra. The three spectra with reasonable quality can be obtained within 11 days using a uniformly 13C,15N-labeled sample at a protein concentration of 1 mM. Unlike the conventional strategy mainly relying on through-bond correlation experiments, the strategy used here mainly uses a through-space correlation experiment (4D 15N,13C-edited NOESY) to obtain intra-residue and sequential correlations, which are separated from other inter-residue NOE correlations using the 3D HNCA and CCH-TOCSY experiments. Similar to the conventional strategy, sequential assignment is achieved from matching intra-residue and sequential correlations. Using this strategy, one can obtain nearly complete backbone assignments and >80% side chain assignments for monomeric proteins < 42 kDa and multimeric proteins < 65 kDa.