The history of the struggle to comprehend fibrinogen is written in individual experiments of individual investigators. Nonetheless, much of the strategy used in approaching its structure can be classified into a few overlapping categories. One class comprises chemical and immunological analyses. The former have yielded considerable progress toward the primary structure and have revealed various types of heterogeneity. The latter have demonstrated both homologies and domains, and may prove invaluable in phylogenetic and biosynthetic studies ; however, by definition, they are at the mercy of the antibody-producing organism. A second strategic class is model building. Early models were based on data from physical (largely hydrodynamic) measurements ; later ones, on morphological observations. More recent efforts have involved dissective approaches, e.g., proteolytic fragmentation. Though models constructed to date are mutually exclusive in detail, their common structural features and the design of experiments used to test them have not yet permitted unequivocal conclusions. Studies of afibrinogenemia, like organ extirpation, can indicate physiological roles but provide little structural information. By contrast, investigations of congenital dysfibrinogenemia are more analogous to perturbation experiments. In addition to providing well defined examples of permissible structural variations, these investigations carry the potential for revealing important structure-function relationships.