Several studies, during the last 20 years, tried to explain the pathogenetic mechanisms of the cyclosporine (CS) induced gingival overgrowth (and in general, of the drugs induced gingival overgrowth), but they are still poorly understood. The relationship between the drug and the different pharmacokinetic variables (dosage, duration of therapy, plasmatic and salivary Cs concentration) is still on discussion. It is accepted that a threshold concentration is necessary, in the gingival tissues, to begin or to enhance the morphostructural changes of the gums, but the total Cs weight, from the beginning of the therapy to the time of clinical examinations, has to be evaluated. The pharmacokinetic variables are associated with many other factors (first of all the oral hygiene score) that are probably connected with the developing of the gingival lesions. Gingival inflammation could be very important in the pathogenesis of gingival overgrowth. It has been shown by several cross-sectional studies a strong association between plaque and gingival lesions, but it is not yet clear if plaque accumulation is a causal factor or a consequence of the morphological gums changes. It would seem that the morphological alterations, in drug-induced gingival overgrowth, could be started by the plaque induced inflammation, and this would lead to an hyperemic and edematous gingival tissue. Oral hygiene (professional and at home) is more difficult and represents an irritation factor that makes the pathological cycle to go on. Other factors, probably connected with the cyclosporine induced gingival overgrowth, are represented by age, gender, genetic predisposition, alterations of gingival connective homeostasis and metabolism, inflammatory alterations, interactions with the growth factors and protective or synergic effects of other drugs.