This review mainly focuses on metformin, and considers oral antidiabetic therapy in kidney transplant patients and the potential benefits and risks of antidiabetic agents other than metformin in patients with chronic kidney disease (CKD). In view of the debate concerning lactic acidosis associated with metformin, this review tries to solve a paradox: metformin should be prescribed more widely because of its beneficial effects, but also less widely because of the increasing prevalence of contraindications to metformin, such as reduced renal function. Lactic acidosis appears either as part of a number of clinical syndromes (i.e., unrelated to metformin), induced by metformin (involving an analysis of the drug's pharmacokinetics and mechanisms of action), or associated with metformin (a more complex situation, as lactic acidosis in a metformin-treated patient is not necessarily accompanied by metformin accumulation, nor does metformin accumulation necessarily lead to lactic acidosis). A critical analysis of guidelines and literature data on metformin therapy in patients with CKD is presented. Following the present focus on metformin, new paradoxical issues can be drawn up, in particular: (i) metformin is rarely the sole cause of lactic acidosis; (ii) lactic acidosis in patients receiving metformin therapy is erroneously still considered a single medical entity, as several different scenarios can be defined, with contrasting prognoses. The prognosis for severe lactic acidosis seems even better in metformin-treated patients than in non-metformin users.