Managing clozapine-treated patients requires clinicians to become familiar with specific medical concerns not typically seen with other antipsychotics. Among the many unique adverse events associated with clozapine treatment is a constellation of fever and immune-mediated pathologies including myocarditis, interstitial nephritis, serositis and drug reaction with eosinophilia and systemic symptoms (DRESS). While the onset of fever during the first weeks of clozapine treatment is a common and often benign occurrence, swift action is necessary with the goal of recognizing and addressing more serious issues or minimizing a treatment interruption when evidence for systemic problems is lacking. The latter concept is important, as fever during the first weeks of therapy may appear in approximately 20% of patients, and therefore is not a reason to permanently discontinue clozapine treatment when there is no evidence for myocarditis, interstitial nephritis, or other systemic drug reactions. Cardiomyopathy is another unusual clozapine-related syndrome that is typically a later development, but presents a distinct group of clinical and ethical challenges when clozapine withdrawal fails to induce meaningful improvements in left ventricular ejection fraction (LVEF). Through a greater understanding of the time course and phenomenology of fever, myocarditis, interstitial nephritis, serositis, DRESS and cardiomyopathy clinicians can make evidence-based decisions about withholding clozapine treatment, and when resumption or rechallenge appears feasible.