The objectives of the present study were (i) to develop an algorithm for predicting the tissue:air partition coefficients (PCs) of volatile organic chemicals (VOCs) and (ii) to apply this algorithm to predict the rat tissue:air PCs of 45 VOCs. The approach consisted of estimating the tissue:air PCs by dividing the tissue solubility of chemicals by their saturable vapor concentrations. The tissue solubility of chemicals was calculated as the sum total of their solubility in neutral lipid, phospholipid, and water fractions of tissues. The rat liver:air, muscle:air, and adipose tissue:air PCs predicted using this algorithm compared well with literature data available for several ketones, alcohols, acetate esters, alkanes, haloalkanes, aromatic hydrocarbons, and diethyl ether. The average ratios between the predicted and experimental values of the tissue:air PC values were 0.94 (liver), 0.93 (muscle), and 1.10 (adipose tissue). The mechanistic algorithm developed in the present study should be useful for predicting tissue:air PCs of VOCs and for verifying the current default assumption of considering tissue:air PCs to be species-invariant.