In a “code stroke” status with the sudden-onset neurologic deficit, stroke is the first diagnosis to investigate to be able to initiate early reperfusion therapy. However, as many as 40% of patients with code stroke involve other conditions (Buck et al., Ann Med 53:420–436, 2021). Up to 15% of patients receiving thrombolytic therapy after a nonenhanced CT have a stroke mimic (Tsivgoulis et al., Stroke 46:1281–1287, 2015). Stroke mimics are conditions that simulate stroke and present with an acute neurological deficit that corresponds to a hypothetical vascular distribution. Although the prevalence of stroke mimics is difficult to quantify, estimates range from as low as 1.4% to as high as 38% of admissions for suspected acute ischemic stroke. In one review including more than 60,000 patients, the rate of stroke mimics was approximately 25% with the most common being peripheral vestibular dysfunction in 23.2%, toxic/metabolic in 13.2%, seizure in 13%, functional disorder in 9.7%, and migraine in 7.76% (Pohl et al. 2021). In the large study of 8187 consecutive patients referred for evaluation of a suspected stroke in the emergency department, 30% were stroke mimics (Merino et al., J Stroke Cerebrovasc Dis 22(8):e397–e403, 2013). In a Canadian EMS study of 960 suspected stroke patients, 43% were subsequently determined to be mimics (Gioia et al., Neurology 86(23):2146–2153, 2016). There is a considerable list of disorders that impose a significant challenge for both neurologists and neuroradiologists, and these include the following: seizures/epilepsy, migraine and headache disorders, hypoglycemia, Susac syndrome, vasomotor disorders, herpes simplex virus encephalitis (HSVE), cerebral amyloid angiopathy (CAA), and venous thrombosis. The most important imaging mimics are conditions associated with cytotoxic edema and false penumbra on perfusion studies (Vilela, Eur J Radiol 96:133–144, 2017). Rapid and accurate neuroimaging triage is essential to guide therapy. High specificity and low sensitivity of multimodal CT for the diagnosis of stroke mimics in the acute setting has been reported (Prodi et al., AJNR Am J Neuroradiol 43(2):216–222, 2022). Among the different multimodal CT techniques, CTP was the most useful in the detection of stroke mimics (Prodi et al., AJNR Am J Neuroradiol 43(2):216–222, 2022). The major disadvantages of multimodal MRI in an emergency setting are its limited availability and longer acquisition time compared to CT. The opposite of stroke mimics is known as “stroke chameleons” (Moulin and Leys, Curr Opin Neurol 32(1):54–59, 2019). These are acute strokes that present clinically resembling a different disorder. While stroke mimics are considered clinical false positives, stroke chameleons represent false negatives of stroke presentations. Stroke mimics can result in unnecessary stroke treatment, particularly IV thrombolysis, while stroke chameleons may delay or prevent patients from receiving the appropriate management. The hospital rate for stroke chameleons can be as high as 40%. The most common clinical presentation of “stroke chameleons” is altered mental status resembling an encephalopathic syndrome and disorders of somatic sensation. Other confounding clinical presentations may include syncope, headache, vertigo, dizziness, hypertensive emergency, signs of systemic infection, and acute coronary syndrome. Imaging is crucial for accurately diagnosing stroke chameleons, with diffusion-weighted MR imaging’s high sensitivity for acute ischemia being essential.