Saccharomyces cerevisiae is considered as a model organism for the investigation of cellular and molecular processes and gene regulation. Specifically, the response of S. cerevisiae to increase in osmolarity of the external medium (osmoadaptation) is a model adaptation process. The first mathematical model of volume changes in S. cerevisiae due to osmolarity has been proposed as early as 1983 by Schwartz and Diller (Cryobiology 20(5):542-552). Since then, both experimental and computational methods in biology have progressed dramatically. Especially in recent years, the study of response to hyperosmotic stress in S. cerevisiae by systems biology approaches has advanced rapidly. However, a holistic understanding of osmoadaptation combining environmental conditions, cellular preconditions, biophysical processes, molecular and biochemical network dynamics, has not yet been reached. Here, we review recent advances in the investigation of different aspects of osmoadaptation and discuss them with respect to an integrated view. This leads us to critically evaluate how to approach the goal of such an integrated view.