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Takotsubo syndrome (TTS) is a recently identified acute heart syndrome, characterized by regional wall motion abnormalities not justified by the presence of significant coronary artery obstruction. Clinically, TTS closely resembles acute coronary syndromes (ACS) and therefore differential diagnosis may be an important obstacle for its correct clinical management. The prevalence of TTS is estimated to be around 2% of acute myocardial infarctions, and the number of diagnoses has increased in recent years, possibly reflecting our growing understanding of this condition. Given the similarities between TTS and ACS, clinical presentation in these patients is equivocal. However, numerous peculiar traits have been observed, such as the greater prevalence in postmenopausal women and the presence of stressful triggers. Many pathogenetic hypotheses for TTS, such as catecholamine overload and microvascular dysfunction, have been proposed. None of these have been capable of independently explaining the underlying mechanisms. The diagnostic criteria proposed by the Heart Failure Association of the European Society of Cardiology represent a novel attempt to introduce semiquantitative parameters, yet further scientific validation is needed. Contrary to previous opinions, TTS is not always benign, considering the relatively high prevalence of acute complications, an estimated in-hospital mortality similar to that of acute myocardial infarction (1–8%), and a significant rate of recurrences and persistence of symptoms. Clinical management of TTS has been largely based on empirical experience related to ACS, and therefore pharmacological strategies are partially overlapping. An issue of the utmost importance is the lack of randomized prospective data validating diagnostic criteria, risk stratification, and specific therapeutic approaches.