A review of hydrophobic interaction chromatography (HIC) of proteins and theories for predicting protein retention time in HIC is given in this paper. A brief description of HIC, hydrophobic interactions and amino acid and protein hydrophobicity is presented and different approaches and models for explaining the retention mechanism of proteins and predicting protein retention time in HIC are described. By using these models it is possible to test different operating conditions for the purification of a target protein and to select the best conditions.