Tree species are exposed to single and combined forms of stress capable of inducing severe changes in plant functioning and survival. Climate change and other human disturbance continue to introduce novel combinations of stressors in forest ecosystems that make predicting their impact exceedingly difficult. In this chapter, we examine the causes and consequences of combined stresses in forest ecosystems. We discuss the significance of a range of abiotic and biotic factors responsible for various impacts on forest ecosystems, including long-term decline and episodic forest collapse. A generalized framework is presented that helps elucidate the contributions of primary, secondary, conditioning, and anthropogenic factors in determining levels of physiological stress in trees. The intensity, frequency, and duration of the constitutive stressors can determine the effect of other stress factors, thereby mediating the importance of singular and multiple factors in defining physiological distress and recovery. The importance of understanding the mechanistic basis for observed stress responses is discussed in light of the challenges associated with predicting impacts from multiple stressors.