Two Tenofovir pro-drugs are available for the treatment of HIV and HBV infection. Tenofovir Alafenamide (TAF) was clinically developed as a safer alternative to the older Tenofovir Disoproxil Fumarate (TDF) as the latter was consistently found to be associated to proximal renal tubule dysfunction and decrease in bone mineral density (BMD). As compared to TDF, the pharmacological properties of TAF are such that a more active drug is delivered into target cells while much less is measurable in general circulation. This translates into an antiretroviral action comparable to TDF with a significantly lower impact on proximal renal tubular function and bone structural integrity. The lipid-lowering effects of TDF as well as its lesser tendency to be associated to undesired body weight increase have raised some doubts about the substitution of TDF with TAF. Both issues, whose genesis is multifactorial, are strictly linked to the hypothesis of increased cardiovascular risk that might follow the switch from TDF to TAF. However, the long-term impact of decreasing renal function on cardiovascular risk must also be considered, especially in aging patients. It is thus a matter of balance: while the action on modifiable behavioural variables may well reduce lipid levels and body weight, the permanent dysfunctional pressure exerted by TDF on the proximal renal tubule could cause irreversible damage to both kidneys and bones. Therefore, all things considered, avoidance of TDF, particularly when aging patients are concerned, appears the preferable approach.