Therapy with i.v. calcitriol (CLT), that had been the mainstay of the cure of severe secondary hyperparathyroidism (SHPT) for many years, is often hindered by the occurrence of hypercalcemia, that requires discontinuation of the drug with consequent rebounding of the parathyroid hormone (PTH) oversecretion. To circumvent this shortcoming, CLT-analogs with less calcemic effects with respect to CLT have been developed. One of these analogs, paracalcitol (PCLT), proved to be at least as powerful as CLT in decreasing serum PTH, but it still remains endowed with some calcemic effect as the parent compound. Meanwhile, calcimimetics (CaMs) drugs targeting the calcium-sensing receptors on the PTG, have been marketed woldwide. Cinacalcet (CNC) is a CaM endowed with the unique prerogative to significantly decrease serum PTH while also decreasing serum calcium. Thus, one may attempt to speculate that CaMs may completely replace vitamin D derivatives from the therapeutic arena. Uremic patients, however, suffer from severe deprivation of biological vitamin D effects, that puts them in need of highly dosed vitamin D in order to both ameliorate their bone status and to preserve their general and cardiovascular health. Thus, a combination therapy with PCLT, which has a significant patient-survival advantage over CLT, and CNC seems to be more appropriate than only-one-drug based therapy for SHPT. Such a combination will hopefully result in a better control of SHPT, avoidance of cumbersome hypercalcemia and higher life expectancy for uremic patients than ever before.