Wireless communication has become ubiquitous in the last two decades and has challenged modern communication system designers to innovate rapidly to meet the challenges of transmitting signal efficiently in a wireless medium. There has been outstanding progress in technology in all layers of the communication protocol stack from robust coding and physical layer transmission, more efficient medium access control (MAC) protocol design both from a throughput and from an energy standpoint, rethinking of the transport layer and routing in mobile ad hoc networks and also development of new application layer concepts that exploit the knowledge of the lower layers. This has caused wireless system engineers to rethink the traditional protocol stack designed for wire line communications and instead investigate cross-layer design approaches that can exploit the information across various layers. Cross-layer design relies on advances in signal processing, information theory and wireless networking. In this chapter, we try to highlight the use of cross-layer design for a few selected scenarios including wireless local area networks (WLAN) and cellular transmissions. We also provide some insight into the challenges faced by a cross-layer design approach.