The structural organization of the genome is emerging as a crucial regulator of the cell state, affecting gene transcription, DNA replication, and repair. Over the last twenty years, increasing evidence prompted the development of new experimental techniques to study genome structure. In parallel with the complexity of the novel techniques, computational approaches have become an essential tool in any structural genomics laboratory to analyze and model the data. For biologists to be able to apply the most appropriate modeling approach, it is fundamental to understand the conceptual bases of distinct methods and the insights they can provide. Here, we will discuss recent advances that were possible thanks to 3D genome modeling, discuss their limitations and highlight future perspectives.