BACKGROUND: Neuroimaging studies have made an important contribution to our understanding of headache pathophysiology. This systematic review aims to provide a comprehensive overview and critical appraisal of mechanisms of actions of headache treatments and potential biomarkers of treatment response disclosed by imaging studies. MAIN BODY: We performed a systematic literature search on PubMed and Embase databases for imaging studies investigating central and vascular effects of pharmacological and non-pharmacological treatments used to abort and prevent headache attacks. Sixty-three studies were included in the final qualitative analysis. Of these, 54 investigated migraine patients, 4 cluster headache patients and 5 patients with medication overuse headache. Most studies used functional magnetic resonance imaging (MRI) (n = 33) or molecular imaging (n = 14). Eleven studies employed structural MRI and a few used arterial spin labeling (n = 3), magnetic resonance spectroscopy (n = 3) or magnetic resonance angiography (n = 2). Different imaging modalities were combined in eight studies. Despite of the variety of imaging approaches and results, some findings were consistent. This systematic review suggests that triptans may cross the blood-brain barrier to some extent, though perhaps not sufficiently to alter the intracranial cerebral blood flow. Acupuncture in migraine, neuromodulation in migraine and cluster headache patients, and medication withdrawal in patients with medication overuse headache could promote headache improvement by reverting headache-affected pain processing brain areas. Yet, there is currently no clear evidence for where each treatment acts, and no firm imaging predictors of efficacy. This is mainly due to a scarcity of studies and heterogeneous treatment schemes, study designs, subjects, and imaging techniques. In addition, most studies used small sample sizes and inadequate statistical approaches, which precludes generalizable conclusions. CONCLUSION: Several aspects of headache treatments remain to be elucidated using imaging approaches, such as how pharmacological preventive therapies work, whether treatment-related brain changes may influence therapy effectiveness, and imaging biomarkers of clinical response. In the future, well-designed studies with homogeneous study populations, adequate sample sizes and statistical approaches are needed.