Knowledge of the three-dimensional (3D) atomic structure of materials is essential to a fundamental understanding of their properties. The key to understanding the functionality of many materials, particularly those of commercial and industrial interest, is often hidden in the details at the nanoscale. For this reason, it is very important to choose the right strategy to analyze the structure of challenging materials with complex disordered framework structures, or of the layered materials that are the subject of this thesis. Structure analysis of beam-sensitive or uniquely disordered materials can be complicated. Although there are already existing methods such as X-ray powder diffraction (XRPD), the data may exhibit reflection overlap or other problems that make structure determination difficult. To overcome these limitations for nanocrystalline materials, complementary characterization techniques can be used. Here, I will focus on 3D electron crystallography (continuous rotation electron diffraction and high-resolution electron microscopy) methods that have grown during the past years as hybrid methods for structure determination. Based on the presented materials, I will also emphasize that any kind of challenges can be a driving force for method development.  Furthermore, some of the insights gained lead to better understanding of how to collect and process 3D electron diffraction data, which could be applied to make data collection of challenging samples easier and obtain higher quality structure refinements from the data. Finally, I will try to describe the general procedures for ab initio structure elucidation of disordered nanocrystals and layered materials.