Nonplanar building blocks make better organic frameworks. Stacking of layered, two-dimensional metal- or covalent organic frameworks (MOFs and COFs) has provided a wide range of porous and crystalline materials with interesting magnetic, optoelectronic, and catalytic properties. The eclipsed, face-to-face arrangement between molecular building blocks is usually believed to maximize the dispersive interaction for self-association and thus planar polycyclic aromatic hydrocarbons are often exploited in the design of new functional 2D organic frameworks. Using the bio-inspired G-quadruplex organic framework as a platform, we elucidated the intricate balance between molecular non-planarity and pi-stacking interaction in determining the crystallinity of 2D frameworks.