Embodiments are described for systems and methods that optimize large-scale data transfers over a wide area network by providing a data transmission protocol stack comprising a TCP layer that exchanges data processed by a host, and an IP layer that transports datagrams encapsulating the data to routers in the WAN, and a UDP-based transmission layer within the data transmission protocol stack that interfaces with the TCP layer and transmits data and control packets between the host and receivers of the WAN using a unicast duplex protocol. The stack has a WAN optimization components layer that interacts with the UDP-based transmission layer and provides transport protocol optimization through the UDP-based transmission layer and certain data de-duplication, compression, link aggregation, and application awareness functions.