The ever-increasing demand on developing layered materials for practical applications, such as electrochemical energy storage, responsive materials, nanofluidics, and environmental remediation, requires the profound understanding and artful exploitation of interlayer engineering or intercalation chemistry. The past decade has witnessed the massive exploration of a recently discovered 2D materialtransition metal carbides, carbonitrides, and nitrides (referred to as MXenes), which began to take hold of a myriad of applications owing to the abundant possibilities on their compositions and intercalation states. However, application-targeted manipulation of the material performance of MXenes is constrained by the dearth of deep comprehension on fundamental intercalation chemistry/physics. To this end, the aim of this review is to provide a holistic discussion on the intercalation chemistry in MXenes and the physical properties of MXene intercalation compounds. On the basis of this, potential solutions for the challenges confronted in the synthesis, tuning of material properties, and practical applications are proposed, which are also expected to reinvigorate the exploration of layered materials that are similar to MXenes.