The preservation of high-quality biospecimens and associated data for research purposes is being performed in variety of academic, government, and industrial settings. Often these are multimillion dollar operations, yet despite these sizable investments, the economics of biobanking initiatives is not well understood. Fundamental business principles must be applied to the development and operation of such resources to ensure their long-term sustainability and maximize their impact. The true costs of developing and maintaining operations, which may have a variety of funding sources, must be better understood. Among the issues that must be considered when building a biobank economic model are: understanding the market need for the particular type of biobank under consideration and understanding and efficiently managing the biobank's "value chain," which includes costs for case collection, tissue processing, storage management, sample distribution, and infrastructure and administration. By using these value chain factors, a Total Life Cycle Cost of Ownership (TLCO) model may be developed to estimate all costs arising from owning, operating, and maintaining a large centralized biobank. The TLCO approach allows for a better delineation of a biobank's variable and fixed costs, data that will be needed to implement any cost recovery program. This article represents an overview of the efforts made recently by the National Cancer Institute's Office of Biorepositories and Biospecimen Research as part of its effort to develop an appropriate cost model and cost recovery program for the cancer HUman Biobank (caHUB) initiative. All of these economic factors are discussed in terms of maximizing caHUB's potential for long-term sustainability but have broad applicability to the wide range of biobanking initiatives that currently exist.