A broad spectrum of individuals with intellectual and developmental disabilities (I/DD) exhibit self-directed behavior that has the capacity to produce tissue injury. Different forms of self-injury (e.g. self-biting, self-hitting, head-banging) may partially segregate in specific neurodevelopmental disorders, although there is also significant overlap. For example, individuals with Prader-Willi syndrome typically pick at their skin, whereas those with Lesch-Nyhan syndrome bite themselves, while individuals with autism exhibit an array of self-injurious behaviors (self-hitting, self-biting, head-banging). Many individuals have "preferred" forms and target locations, and their self-injurious acts can be highly repetitive and stereotyped. Such structural characteristics can differ substantially between individuals even when they have the same genetic syndrome or type of neurodevelopmental disorder. Furthermore, self-injurious behavior (SIB) emerges in a variety of environmental contexts, and may be closely associated with impoverished institutional environments and/or emotional distress, suggesting that. these may be common establishing conditions. It is worth noting that SIB is also seen in animals under a variety of circumstances, including laboratory models, domestic pets, and animals kept in zoos or farms. Thus, the etiology and expression of SIB is not unique to humans. Overall, these observations raise a variety of questions about the etiology and expression of self-injury. Do the various forms of self-injury represent the same or different phenomena across the different groups? Are there common underlying mechanisms, or does each pattern of SIB represent a distinct form of predisposing neuropathology? Because self-injury is prevalent across disparate diagnostic groups, is there reason to believe that perturbation of common biological mechanisms make it more likely that SIB will emerge? This question could be restated to ask whether risk factors (which seem to vary widely at the phenomenological level) are mediated through some common pathophysiological mechanism(s) such that biological vulnerabilities - regardless of diagnostic differences - can be identified to estimate developmental risk for SIB. The ultimate goal of a developmental account is to promote prevention in the form of risk reduction. Our specific purpose in writing this chapter is to selectively review the research evidence for "risk factors" that promote vulnerability for SIB specific to I/DD, and then suggest that our current approach to understanding SIB risk has been limited by relying for too long on conventional prevalence ratio study designs. We argue that adopting approaches informed from bench studies of risk factors may help move us forward faster in understanding which individuals with I/DD are likely to develop SIB and the circumstances under which it will most likely occur.