An analysis is presented of selected aspects of stress theory and research in biology and medicine, both before and after the introduction of Selye's stress formulations, which have been of major importance in the development and popularity of this research area. An attempt is made to explore some possible sources of present confusion and controversy in the stress field, with a view to the development of new research strategies that may enable us to clarify, update, and revise stress concepts and to facilitate future progress. In particular, it is suggested that an experimental reevaluation of the concept of the non-specificity of pituitary-adrenal cortical response is a matter of particular strategic importance, if we are to move out of the present prolonged period of stalemate and confusion over stress theory and terminology. Recent experimental studies which suggest that the nonspecificity concept may have been applied erroneously to lower level physiological mechanisms, rather than to higher level psychological processes, are reviewed. The possible implications of this development are discussed in terms of clarifying current concepts and providing guidelines for future lines of approach in stress research.