It has been proposed that the molecular and physiological systems that regulate biological functions impose costs and constraints that are fundamental to the understanding of variation in life histories. In particular, studies of oxidative stress emphasize how evolutionary contingency can impose novel trade-offs for organisms, and how this may create or eliminate functional linkages between traits. Here, we critically assess the conceptual and empirical basis for these claims and what they mean for the study of life-history variation. Two key challenges are to go beyond the current focus on single components of regulatory systems, assessed at single points in time, and to establish the importance of trait- and stage-specific nutrient requirements for the functional linkage between life-history traits. Furthermore, future progress will critically depend on the replication of laboratory studies in natural settings to target the complexity of trade-off regulation in the wild.