Due to their well-established efficacy and safety, stimulants are the drugs of first choice if medication for attention-deficit hyperactivity disorder (ADHD) is required. Nevertheless, for some individuals other, non-stimulant treatments are needed for several reasons. If so, atomoxetine is recommended as a second-line treatment. In addition, several tricyclic antidepressants, such as desipramine or imipramine, as well as alpha-2 agonists, especially clonidine or bupropion, might be efficient in treating ADHD, in particular in specific co-morbid conditions. Despite the fact that non-stimulant treatments in ADHD are usually well-tolerated with side effects being mostly moderate and transient, special safety aspects and precautions, specific for each drug, have to be considered whenever a non-stimulant treatment is chosen. This review focuses on the tolerability, occurrence of adverse events, precautions required to prevent severe adverse events, and essential pharmacological interaction in the treatment of ADHD symptoms by non-stimulants.