In modern drug discovery process, ADME/Tox properties should be determined as early as possible in the test cascade to allow a timely assessment of their property profiles. To help medicinal chemists in designing new compounds with improved pharmacokinetics, the knowledge of the soft spot position or the site of metabolism (SOM) is needed. In recent years, large number of in silico approaches for metabolism prediction have been developed and reported. Among these methods, QSAR models and combined quantum mechanics/molecular mechanics (QM/MM) methods for predicting drug metabolism have undergone significant advances. This review provides a perspective of the utility of QSAR and QM/MM approaches on drug metabolism prediction, highlighting the present challenges, limitations, and future perspectives in medicinal chemistry.