To designate former United States Route 66 as "America's Main Street" and authorize the Secretary of the Interior to provide assistance.

Designates portions of the highway formerly designated as U.S. Route 66 that remain in existence as "America's Main Street."

Directs the Secretary of the Interior to: (1) establish the Office for the Preservation of America's Main Street; and (2) designate National Park Service officials stationed at locations convenient to the States in which a portion of Route 66 is located and interested persons in such States to perform Office functions. Requires the Office to: (1) support efforts of State and local public and private persons and entities in such States to preserve Route 66 by providing technical assistance, participating in cost-sharing programs, and making grants and loans; (2) act as a clearinghouse for communication among Federal, State, and local agencies and private persons and entities interested in the preservation of Route 66; and (3) assist such States in determining the appropriate form of and establishing and supporting a non-Federal entity or entities to perform the Office's functions after it is terminated. Authorizes the Office to: (1) enter into cooperative agreements; (2) accept donations; (3) provide cost-share grants; (4) provide technical assistance in historic preservation and fundraising; and (5) conduct research.

Requires the Office: (1) to sponsor a road sign program on Route 66 to be implemented on a cost-sharing basis with State and local organizations; (2) to provide assistance in the preservation of Route 66 that is compatible with the idiosyncratic nature of the highway; (3) not to prepare an overall management plan for Route 66, but to cooperate with the States and local public and private persons and entities in developing local preservation plans to guide efforts to protect the most important or representative resources of Route 66; (4) to develop a technical assistance program in the preservation of Route 66, including guidelines for setting priorities for preservation needs; and (5) to coordinate a program of historic research, curation, preservation strategies, and collection of oral and video histories of Route 66 designed for continuing use and implementation by other organizations after the Office is terminated.

Makes available cost-share grants for the preservation of Route 66 for resources that meet the guidelines under the program.

Authorizes appropriations.

Terminates the Office ten years after the date of enactment of this Act.