The observation that enhanced mitochondrial transmembrane potential is a prevalent tumor cell phenotype has provided the conceptual basis for the development of mitochondrial targeting as a novel therapeutic strategy for (photo)chemotherapy of neoplastic diseases. Because the plasma transmembrane potential is negative on the inner side of the cell, and the mitochondrion transmembrane potential is negative on the inner (matrix) side of this organelle, extensively conjugated cationic molecules (dyes) displaying appropriate structural features are electrophoretically driven through these membranes and tend to accumulate inside energized mitochondria. As a result of the higher mitochondrial transmembrane potential typical of tumor cells, a number of cationic dyes preferentially accrue and are retained for longer periods in the mitochondria of these cells as compared to normal cells, and this differential in both drug loading and retention brings about the opportunity of attacking and destroy tumor cells with a high degree of selectivity. It is reasonable to infer that, for desirable degrees of tumor cell selectivity to be achieved the mechanisms of cellular uptake and intracellular distribution of any putative mitochondrial drug candidate must be primarily controlled by transmembrane potentials, with just minor contributions arising from lipophilic partitioning or any other competitive phenomena. Here we describe how the lipophilic/hydrophilic character of five model mitochondrial drug candidates (i.e. the methyl, n-propyl, i-propyl, n-pentyl, and n-octyl ester derivatives of rhodamine-110) affect the degree of specificity with which these dyes localize in energized mitochondria, and the extent to which transmembrane potentials effect their mitochondrial localization and subcellular distribution. Our results have indicated that the range of lipophilic/hydrophilic character associated with a high degree of potential-driven mitochondrial specificity tends to decrease to negligible levels when the lipophilic character of the dye approaches values of octan-1-ol/water partition coefficient close to two orders of magnitude above that of the methyl ester derivative.