Severe agitation in patients with delirium may be difficult for clinicians’ management because of problems of differential diagnosis and treatment. Regrettably, theory and guidelines concerning this issue may fail to cover the incredible complexity of clinical practice. Our aim is to describe three cases of delirium from our real-life clinical experience, with a specific focus on their complexity as far as differential diagnosis and psychopharmacological treatment are concerned. In clinical practice, as shown by the three cases we describe, the etiology of delirium is various and mixed, lab analysis are not specific and it is not possible to exactly assess which kind of substances were used by patients. New drugs and smart drugs are not yet detectable by our urine analysis, and their effects, interaction with prescription drugs and pharmacokinetics are not well known. With the aim to obtain a successful sedation and to calm the patient, in our cases, we needed to use a pharmacological combined approach (benzodiazepines, first and second generation antipsychotics) with different routes of administration and, when inevitable, physical restraint.