Lanthanides, the 14 4f-block elements plus Lanthanum, have been extensively used to study the structure and biochemical properties of metalloproteins. The characteristics of lanthanides within the lanthanide series are similar, but not identical. The present research offers a systematic investigation of the ability of the entire Ln3+ series to substitute for Ca2+ in biological systems. A well-calibrated DFT/PCM protocol is employed in studying the factors that control the metal selectivity in biological systems by modeling typical calcium signaling/buffering binding sites and elucidating the thermodynamic outcome of the competition between the "alien" La3+/Ln3+ and "native" Ca2+, and La3+ - Ln3+ within the lanthanide series. The calculations performed reveal that the major determinant of the Ca2+/Ln3+ selectivity in calcium proteins is the net charge of the calcium binding pocket; the more negative the charge, the higher the competitiveness of the trivalent Ln3+ with respect to its Ca2+ contender. Solvent exposure of the binding site also influences the process; buried active centers with net charge of -4 or -3 are characterized by higher Ln3+ over Ca2+ selectivity, whereas it is the opposite for sites with overall charge of -1. Within the series, the competition between La3+ and its fellow lanthanides is determined by the balance between two competing effects: electronic (favoring heavier lanthanides) and solvation (generally favoring the lighter lanthanides).