Over activation of the canonical NF-kappaB pathway can result in increased cell proliferation and inflammatory response leading to serious health problems including chronic inflammatory diseases and cancers (Lawrence 2009). In its resting state, NF-kappaB is kept sequestered in the cytoplasm through its interaction with IkappaBalpha (Lawrence 2009). Activation of the IKK complex marks IkappaBalpha for polyubiquitination proteasomal degradation, resulting in release of the NF-kappaB dimer and its subsequent translocation into the nucleus and activation of target genes (Lawrence 2009). Evidence suggesting that an interaction between NEMO and IkappaBalpha directs pleiotropic IKKbeta to IkappaBalpha designates this interaction as a promising target for inhibition of the canonical NF-kappaB pathway (Schrofelbauer 2012). This work presents a biophysical study of the interaction between NEMO and IkappaBalpha. Biochemical and NMR experiments identified the minimal structural domains necessary for this interaction. A series of circular dichroism experiments were conducted to examine changes in secondary structure upon complex formation. A molecular envelope of the complex was constructed from small angle x-ray scattering data, and a bioinformatics and molecular modeling approach was used to construct a model to fit this molecular envelope. These results provide valuable information on this novel protein-protein interaction. The model of the complex within its molecular envelope provides insight into the nature of complex formation between NEMO and IkappaBalpha and can be utilized in generating a high-resolution structure by x-ray crystallography. Preliminary NMR results can be optimized for elucidation of complex formation at the residue level.