Computational studies of molecules always require consideration of two competing factors that determine the reliability and feasibility of the computation, i.e. accuracy and computational cost. Especially when studying large molecular systems such as enzymes, how to find the best compromise between these two factors becomes a matter of major concern. The most promising route to minimising the computational cost, while maintaining good reliability of computational outcomes, is to define subsystems within a system and then apply different levels of computational methods to different subsystems. The ONIOM (Our own N-layer Integrated molecular Orbital and molecular Mechanics) method enables such hybrid calculations. In particular, the two-layer ONIOM QM/MM scheme or ONIOM2(QM:MM), which combines quantum mechanics (QM) and molecular mechanics (MM) methods, is useful for the investigation of chemical reactions occurring in complex molecular systems such as enzymes. In this chapter, some of the key concepts used in ONIOM2(QM:MM) calculations are reviewed for students and researchers beginning to explore enzymes computationally. A few recent applications of the ONIOM method to enzymatic reactions are also showcased to provide specific examples that we hope will facilitate understanding of the method.