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The cost of reproduction is of fundamental importance in life-history evolution. However, our understanding of its mechanistic basis has been limited by a lack of detailed functional information at all biological levels. Here, we identify, evaluate and integrate recent studies in five areas examining the proximate mechanisms underlying the cost of reproduction. Rather than being alternate explanations, hormonal regulation and intermediary metabolism act in concert and have an overarching influence in shaping the cost of reproduction. Immune function is compromised by reproduction, as is resistance to environmental stress. These studies not only provide new information about mechanisms that comprise “the cost,” but also hint at an underlying evolutionarily conserved causal mechanism.