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In this paper, we study two fundamental issues of cooperative communications in distributed wireless networks, namely when to cooperate and whom to cooperate with. In specific, we focus on cross-layer medium access control (MAC) protocol design with beneficial node cooperation. To increase long-term network throughput, we propose an optimal grouping strategy for relay node selection, and devise a greedy algorithm for MAC protocol parameter refinement. Quantitative relationships among the channel state, payload length, protocol overhead, and cooperation gain are illustrated. Simulation results show that the proposed approach can effectively exploit beneficial cooperation, thereby improving system performance.