Understanding long-term insect and pathogen effects on host tree physiology can help forest managers respond to insect and pathogen outbreaks, and understand when insect and pathogen effects on tree physiology will be exacerbated by climate change. Leaf-level physiological processes modify the carbon (C) and oxygen (O) stable isotopic composition of elements taken up from the environment, and these modifications are recorded in tree-rings (see Chaps. 10.1007/978-3-030-92698-4_9, 10.1007/978-3-030-92698-4_10, 10.1007/978-3-030-92698-4_16 and 10.1007/978-3-030-92698-4_17). Therefore, tree-ring stable isotopes are affected by both the tree’s environment and the tree’s physiological responses to the environment, including insects and pathogens. Tree-ring stable isotopes provide unique insights into the long-term effects of insects and pathogens on host tree physiology. However, insect and pathogen impacts on tree-ring stable isotopes are often overlooked, yet can substantially alter interpretations of tree-ring stable isotopes for reconstructions of climate and physiology. In this chapter, we discuss (1) the effects of insects(defoliators, wood-boring, leaf-feeding), pests (parasitic plants), and pathogens(root and foliar fungi) on hostphysiology (growth, hormonal regulation, gas exchange, water relations, and carbon and nutrient use) as they relate to signals possibly recorded by C and O stable isotopes in tree-rings, (2) how tree-ring stable isotopes reveal insect and pathogen impacts and the interacting effects of pathogens and climate on hostphysiology, and (3) the importance of considering insect and pathogen impacts for interpreting tree-ring stable isotopes to reconstruct past climate or physiology.