The purpose of this paper is to present a novel built-in Clock Domain Crossing (CDC) test and diagnosis methodology for Globally Asynchronous, Locally Synchronous (GALS) systems. The methodology allows design and prototype validation, low maintenance and repair costs, and production / lifetime at-speed test. Moreover, high resolution diagnosis is obtained, to identify which device(s) and/or communication channel(s) is (are) faulty. This is not trivial in GALS systems, for which the CDC issue is challenging. The underlying principle of the proposed methodology is to embed a CDC test and diagnosis (CDC T&D) structure in each locally synchronous domain. Complete device-to-device communication channels are tested, including transceivers, buses, and board connectors. Identical test patterns (generated to detect static (stuck-at, shorts and open faults) and dynamic (crosstalk) faults) are used in each FPGA. The proposed CDC T&D methodology is validated in a case study, the acquisition electronics of a complex multi-board, multibus, multi-FPGA (nine Xilinx™ xc2v4000-4bf957) system. Test and validation results are presented.