Many cells in the immune system communicate using proteins called cytokines, which consist of distinct structural and functional families with roles in immunology, endocrinology, and cellular biology. A subset of cytokines, interferons, can be classified into three types (type I, II, and III) and have been explored for decades as therapeutics but have been plagued by issues ranging from off-target delivery to dramatic variations in patient response. The latter issue has presented the field of interferon biology with an interesting conundrum – genome-wide association studies of patients who failed to respond to interferon treatment identified a genetic region within the type III interferon locus that leads to expression of a protein called IFNλ4, implicating expression of this protein as the barrier for treatment. Since its discovery in 2013, structural and functional questions have continued to build around IFNλ4, but the inability to produce useful quantities of the protein has drastically limited experimental progress. This work presents the first method for robust expression of IFNλ4 and enables the solution of its ternary extracellular signaling complex, providing a structural basis of IFNλ4 function and lending insights into its dysfunction. Chapter 1 presents a discussion of interferons as therapeutics and a thorough discussion of therapeutic implications of type III interferons and specifically IFNλ4. Excerpts of this Chapter appear as published in Trends in Biochemical Science under the title “Recent and future perspectives on engineering interferons and other cytokines as therapeutics”. Chapter 2 describes a method for high-yield expression and purification of IFNλ4, accompanied by select in vitro data exploring its extracellular function. Chapter 3 explores the use of molecular modeling and simulation to study and engineer cytokine-receptor complexes, specifically the ternary IFNλ complex, towards solving the structure of the IFNλ4 receptor complex. This Chapter appears as published in Biophysical Journal, titled “Molecular analysis of the type III interferon complex and its application in protein engineering”. Chapter 4 reports the structure of IFNλ4 in complex with its receptors IFNλR1 and IL10Rβ solved by cryogenic electron microscopy, as well as the structure of IFNλ3 in complex, and includes a comparison of the two related but distinct structures. Chapter 5 includes a thorough discussion of these findings and outlines future research questions for IFNλ4. In total, these results resolve the decade-long expression and purification bottleneck of IFNλ4 and provide structural and mechanistic insight into both its function and dysfunction in the human immune system. Future studies should be focused on the systemic impact of IFNλ4 expression and its role in the pathology of multiple diseases, with a specific focus on developing structure-informed treatments for patients with poor clinical outlooks due to IFNλ4 expression.