A familiar situation in migraine treatment is the patient with an initial positive response to prophylactic drug therapy who later experiences relapse. The goals of this paper are to provide a theoretical framework to help doctors think about this problem, to evaluate factors and response patterns that may be associated with different causes of relapse, and to suggest clinical strategies that may aid in its management. Six key explanations for loss of benefit from prophylactic therapy are: (1) pharmacokinetic, pharmacodynamic, and behavioral drug tolerance; (2) non-specific or placebo effects; (3) natural variability in disease activity; (4) disease progression; (5) inaccurate recall of treatment effects; and (6) drug delivery problems. Current options for patients who experience loss of benefit from prophylactic therapy include traditional techniques such as switching, re-trying, rotating, or combining drugs. Selected behavioral and environmental treatment techniques might also be useful. We describe a practical, structured approach to evaluation and management of relapse with migraine prophylaxis.