The word Chesepiooc is an Algonquian word meaning "Great Shellfish Bay." Chesapeake Bay was once known for its great seafood production, especially blue crabs, clams and oysters. The plentiful oyster harvests led to the development of the Skipjack, the State Boat of Maryland, which is the only remaining working boat type in the United States still under sail power. Today, the body of water is less productive than it used to be, because of runoff from urban areas (mostly on the western shore) and farms (especially on the eastern shore), overharvesting, and invasion of foreign species. The bay though, still yields more fish and shellfish (about 45,000 short tons or 40 000 tonnes yearly) than any other estuary in the United States.

The Bay is famous for its rockfish, also known as striped bass. Once on the verge of extinction, rockfish have made a significant comeback and are now able to be fished in strictly controlled and limited quantities.

The Bay serves as the predominant source of eel in the United States.

Specific notable fish are the Cownose Ray, Eastern Oyster, Sandbar shark, and Atlantic silverside. It is about the northern limit of the Harvestfish.

In 2005, local governments began debate on the introduction to certain parts of the Bay of a species of asian oyster, to revive the lagging shellfish industry.

The depletion of oysters due to overharvesting and damaged habitat has had a particularly harmful effect on the quality of the Bay. The Bay's oyster industry has also suffered from two diseases: MSX and dermo. Oysters serve as natural water filters, and their decline has further reduced the water quality of the Bay. Water that was once clear for fathoms is now so turbid that a wader may lose sight of his feet before his knees are wet.

Efforts of local and state government, and the Chesapeake Bay Foundation, to restore or at least maintain the current water quality have had mixed results. One particular obstacle to cleaning up the Bay is that much of the polluting substances arise far upstream in tributaries lying within states far removed from the Bay itself.

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