Complex human diseases commonly arise from deregulation of cell growth, metabolism, and/or gene expression. Yeast is a eukaryal model organism that is widely used to study these processes. Yeast systems biology benefits from the ability to exert fine experimental control over the cell growth rate and nutrient composition, which allows orthogonal experimental design and generation of multi-omics data at high resolution. This has led to several insights on the principles of cellular physiology, including many cellular processes associated with complex human diseases. Here we review these biological insights together with experimental and modeling approaches developed in yeast to study systems biology. The role of yeast systems biology to further advance systems and personalized therapies for complex diseases is discussed.