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The dynamic three-dimensional (3D) organization of the human genome (the "4D Nucleome") is closely linked to genome function. Here, we integrate a wide variety of genomic data generated by the 4D Nucleome Project to provide a detailed view of human 3D genome organization in widely used embryonic stem cells (H1-hESCs) and immortalized fibroblasts (HFFc6). We provide extensive benchmarking of 3D genome mapping assays and integrate these diverse datasets to annotate spatial genomic features across scales. The data reveal a rich complexity of chromatin domains and their sub-nuclear positions, and over one hundred thousand structural loops and promoter-enhancer interactions. We developed 3D models of population-based and individual cell-to-cell variation in genome structure, establishing connections between chromosome folding, nuclear organization, chromatin looping, gene transcription, and DNA replication. We demonstrate the use of computational methods to predict genome folding from DNA sequence, uncovering potential effects of genetic variants on genome structure and function. Together, this comprehensive analysis contributes insights into human genome organization and enhances our understanding of connections between the regulation of genome function and 3D genome organization in general., Competing Interests: Conflicts of interest Job Dekker is a member of the scientific advisory board of Arima Genomics, San Diego, CA, USA and Omega Therapeutic, Cambridge, MA, USA. Sheng Zhong. is a founder and shareholder of Genemo, Inc., San Diego, CA, USA Bing Ren has equity in Arima Genomics Inc., San Diego, CA, USA and Epigenome Technologies, San Diego, CA, USA Clair Marchal is the director and founder of In silichrom ltd.