The ideal experimental design depends on the biological mechanisms and physiology under investigation. Classical metabolic data provides insight into clearance of specific metabolic pools, but recent discoveries in epigenetic provide the opportunity for long-term responses to diet. Arguably, the most complete experimental design would determine the effect of a dietary treatment over entire lactations, multiple lactations, and possibly over multiple generations. However, these approaches are not practical and arguably other interactions are of greater importance. Experimentally the time course of response to a treatment is very important to provide mechanistic insight into the primary mechanism and secondary adaptations. Both primary mechanisms and secondary adaptations are biologically relevant and application of time-series analysis in experiments may provide key insight in understanding theses mechanisms. In our own work with milk fat depression we have determined the time course of rumen response to diet changes and mammary response to bioactive fatty acids. This information has been invaluable to efficient experimental design and increasing confidence in mechanisms. Lastly, a common goal is to determine the expected response to a treatment. Temporal adaptation is one factor to consider, but many other interactions such as composition of the basal diet (e.g., high vs. low fiber) and physiological state of the cow (including level of intake and production) are also extremely important factors. Arguably, testing treatments over several conditions with adequate, but not excessive, treatment durations would optimize the accuracy of the predicted response when a treatment is applied in practice.