Endocarditis is a life-threatening, relatively rare disease caused by an infection of the endocardial epithelium of the heart. Its clinical presentation is highly variable, depending on whether it presents acutely, subacutely, or chronically. Also, the wide array of causal etiologies and pathogens makes its diagnosis and treatment complex and challenging. The main etiological agents are S
taphylococci
and S
treptococci
, while fastidious microorganisms are infrequent agents of this pathology. Advancements in the identification of microorganisms with novel molecular techniques have revealed new previously unidentified pathogens. Despite their low frequency, these fastidious pathogens are highly relevant, as they have been associated with a higher rate of complications and mortality. Therefore, it is necessary to be aware of the wide array of clinical presentations and important considerations for the management of patients with subacute endocarditis with atypical microorganisms. In this article, we present a case series involving three different clinical presentations of subacute endocarditis with fastidious microorganisms, which required extensive medical management and surgical valve repair with favorable and unfavorable outcomes. We also engage in a review of the literature on their microbiology, diagnosis, and treatment.