Tampa Bay was designated an "estuary of national significance" by Congress in 1990, paving the way for development of a long-term blueprint for bay restoration through the Tampa Bay National Estuary Program. Tampa Bay is one of 28 estuaries in the National Estuary Program; others in Florida are Sarasota Bay, Charlotte Harbor and Indian River Lagoon.

The Tampa Bay National Estuary Program (TBNEP) was established in 1991 as a partnership of Hillsborough, Manatee and Pinellas counties; the cities of Tampa, St. Petersburg and Clearwater; the Southwest Florida Water Management District; the Florida Department of Environmental Protection; and the U.S. Environmental Protection Agency. As of 2016, Pasco County has also joined the partnership.

In 1998, these and six other partners signed a formal Interlocal Agreement, and ancillary agreements, pledging to achieve the goals of the newly completed Comprehensive Conservation and Management Plan (CCMP) for Tampa Bay, called Charting The Course. The Plan culminated nearly six years of scientific research into the bay's most pressing problems, and reflected broad-based input from citizens, groups and communities with a common interest in a healthy bay as the cornerstone of a prosperous economy.

Upon adoption of the Interlocal Agreement, the Tampa Bay National Estuary Program became simply the Tampa Bay Estuary Program, in recognition of its reorganization as a truly regional alliance.

TBEP continues to coordinate the overall protection and restoration of the bay with assistance and support from its many formal and informal partners. TBEP monitors progress in achieving the goals of the CCMP by regularly summarizing and evaluating information provided by program participants. In 2006, TBEP released the first revision of Charting The Course, assessing progress in implementing the Plan's original goals, and incorporating new or emerging action areas. A second revision was completed in 2017. The current version is here: Charting the Course, 2017 revision.

TBEP leverages the resources of program partners by financing cutting-edge research into key problems impacting the bay; sponsoring demonstration projects to test innovative solutions to these problems; providing "Mini-Grants" to community groups to engage the public in bay restoration; and developing educational programs targeting key segments of the bay community - including teachers, boaters and homeowners.