Uncertainty is a pervasive characteristic of illness. Yet little is known about the individual or situational factors that contribute to perceptions of uncertainty. The present study aims to examine the factors that contribute to perceived uncertainty among parents of a child with an undiagnosed condition. Two hundred sixty-six parents of a child, or children, affected by an undiagnosed medical condition for at least 2 years completed an electronically administered mixed-methods survey assessing theoretical predictors of perceived uncertainty. Multivariate linear regression analyses were used to identify the relationship of key variables to perceived uncertainty. Parents' perceived control and optimism were negatively associated with uncertainty (B = −4.044, P ≤ 0.001, B = −0.477, P ≤ 0.05). Subjective disease severity was positively associated with perceived uncertainty (B = 1.797, P ≤ 0.05). Our findings suggest that parents who experience greater uncertainty feel less control over their child's medical condition, which may lead to less effective coping and poorer adaptation. Parents who are less optimistic or who perceive their child's disease as more severe may benefit most from interventions that target situations where parents perceive the least control, thereby enhancing coping and ultimately, adaptation. Published 2012. This article is a U.S. Government work and is in the public domain in the USA.