Thanks to their superior molecular permeation properties and remarkable selectivity, 2D material nanolaminate membranes (2DMMs) have garnered significant attention as next-generation separation membranes. The performance of 2DMMs is largely determined by nanochannel architecture and microenvironment, which are affected by the surface pattern and physiochemical properties of 2D nanosheets. This review summarizes the nanochemistry strategies for engineering 2D materials and discusses the effect of nanosheet modification on the nanochannel architecture (interlayer space) and surface physiochemical properties (charge, affinity, and hydrophilicity) of the nanolaminate membrane. It also sheds light on the importance of the physical and chemical properties of the nanosheets in tailoring the performance of 2DMMs for selective sieving. We finally discuss the remaining challenges and opportunities associated with the development of 2DMMs.