Fc‐Fusion proteins represent a successful class of biopharmaceutical products, with already 13 drugs approved in the European Union and United States as well as three biosimilar versions of etanercept. Fc‐Fusion products combine tailored pharmacological properties of biological ligands, together with multiple functions of the fragment crystallizable domain of immunoglobulins. There is a great diversity in terms of possible biological ligands, including the extracellular domains of natural receptors, functionally active peptides, recombinant enzymes, and genetically engineered binding constructs acting as cytokine traps. Due to their highly diverse structures, the analytical characterization of Fc‐Fusion proteins is far more complex than that of monoclonal antibodies and requires the use and development of additional product‐specific methods over conventional generic/platform methods. This can be explained, for example, by the presence of numerous sialic acids, leading to high diversity in terms of isoelectric points and complex glycosylation profiles including multiple N‐ and O‐linked glycosylation sites. In this review, we highlight the wide range of analytical strategies used to fully characterize Fc‐fusion proteins. We also present case studies on the structural assessment of all commercially available Fc‐fusion proteins, based on the features and critical quality attributes of their ligand‐binding domains.