Systematic investigation of reactivation-induced memory updating began in the 1960s, and a wave of research in this area followed the seminal articulation of “reconsolidation” theory in the early 2000s. Myriad studies indicate that memory reactivation can cause previously consolidated memories to become labile and sensitive to weakening, strengthening, or other forms of modification. However, from its nascent period to the present, the field has been beset by inconsistencies in researchers’ abilities to replicate seemingly established effects. Here we review these many studies, synthesizing the human and nonhuman animal literature, and suggest that these failures-to-replicate reflect a highly complex and delicately balanced memory modification system, the substrates of which must be finely tuned to enable adaptive memory updating while limiting maladaptive, inaccurate modifications. A systematic approach to the entire body of evidence, integrating positive and null findings, will yield a comprehensive understanding of the complex and dynamic nature of long-term memory storage and the potential for harnessing modification processes to treat mental disorders driven by pervasive maladaptive memories. • We discuss evidence for reactivation-induced memory updating in humans and animals. • Decades of research indicate that memory reactivation can promote updating. • Replication failures raise valid questions about the nature of this phenomenon. • Conditions for inducing memory destabilization require clarification. • Specificity of destabilization triggers might explain discrepant results.