Symmetric homo-oligomers (protein complexes with similar subunits arranged symmetrically) play pivotal roles in complex biological processes such as ion transport and cellular regulation. Structure determination of these complexes is necessary in order to gain valuable insights into their mechanisms. Nuclear Magnetic Resonance (NMR) spectroscopy is an experimental technique used for structural studies of such complexes. The data available for structure determination of symmetric homo-oligomers by NMR is often sparse and ambiguous in nature, raising concerns about existing heuristic approaches for structure determination. We have developed an approach that is complete in that it identifies all consistent conformations, data-driven in that it separately evaluates the consistency of structures to data and biophysical constraints and efficient in that it avoids explicit consideration of each of the possible structures separately. By being complete, we ensure that native conformations are not missed. By being data-driven, we are able to separately quantify the information content in the data alone versus data and biophysical modeling. We take a configuration space (degree-of-freedom) approach that provides a compact representation of the conformation space and enables us to efficiently explore the space of possible conformations. This thesis demonstrates that the configuration space-based method is robust to sparsity and ambiguity in the data and enables complete, data-driven and efficient structure determination of symmetric homo-oligomers