In this chapter, we focus on the energy efficient cooperative communication with random node cooperation for wireless networks. By “random,” we mean that the cooperative nodes for each communication event are randomly selected based on the network and channel conditions. Different from the conventional deterministic cooperative communication where cooperative nodes are determined prior to the communication, here the number of cooperative nodes and the cooperation pattern may be random, which is more practical given the random nature of the channels among the source nodes, relay nodes, and destination nodes. In addition, it is more robust to the dynamic wireless network environment. Starting with a thorough literature survey, we then discuss the challenges for random cooperative communication systems. Afterwards, two examples are presented to illustrate the design methodologies. In the first example, we analyze a simple scheme for clustered wireless networks, where cooperative communication is deployed in the long-haul inter-cluster transmissions to improve the energy efficiency. We quantify the energy performance and emphasize its difference from the conventional deterministic ones. In the second example, we consider the cross-layer design between the physical layer and the medium access control (MAC) layer for the one-hop random single-relay networks. We unify the power control and the relay selection at the physical layer into the MAC signaling in a distributed fashion. This example clearly shows the strength of cross-layer design for energy-efficient cooperative systems with random node collaboration. Finally, we conclude with discussions over possible future research directions.