The idea that adverse life circumstances and negative life events contribute to disorder and disease has long been held. Advances in conceptualizing and defining these conditions under the common label of life stress have led to progress in measuring both the environmental and individual response characteristics that may promote disorder and disease. In general, a substantial and growing research literature supports the basic premise that life stress plays an important role in the development of many psychological and physical problems. Recent research, too, strongly suggests that interest in life stress in relation to health and disease will accelerate over the coming years. Yet debates and controversies remain concerning how to best conceptualize and measure life stress, which presents distinctive challenges for advancing the field. The present review examines the major issues pertaining to these debates, controversies, and challenges, for they will be crucial to resolve if progress is to be made in understanding ways in which life stress may or may not contribute to psychological and physical disorders.