Our purpose was to report on a novel method of identifying variables associated with challenging behaviors in natural interactions between mothers and their adolescents with Fragile X syndrome (FXS). Videotaped interactions of 47 dyads interacting with an iPad game, completing a puzzle, and making a snack and were coded for challenging behaviors by adolescents with FXS, and maternal behaviors that preceded these behaviors. We described the frequencies of adolescent challenging behaviors, then used sequential and survival analyses to identify maternal and adolescent behaviors that preceded self-injurious behavior (SIB) and aggression. Across all the dyads, 109 instances of SIB and 79 instances of aggression were identified during the 30min of recorded interaction. Most of these challenging behaviors occurred during the iPad activity. The sequential analysis indicated that maternal requests for behavioral compliance frequently preceded both SIB and aggression. Survival analyses revealed that the likelihood of SIB or aggression was increased if the mothers requested behavioral compliance after the child engaged in another challenging behavior. Challenging behaviors including SIB and aggression were frequently observed in many participants. The sequential and survival analyses were useful for identifying precursors to these behaviors. Further research is needed to investigate preventative strategies based on the results of sequential and survival analyses.