The understanding of how specific cell types regulate their properties and contribute to tissue function is the basis for understanding human physiology and disease. Recent advances in high throughput technologies have allowed cellular properties of individual cell types to be studied in an unbiased way at hitherto unprecedented depth. However, a major limitation of these studies is that cells must be isolated and often cultured in order to be studied. This is a significant limitation, because the cellular phenotype depends on instructions from other cells in the tissue niche. Therefore, major current challenges are 1) to record changes in gene expression of individual cell types in their tissue context; 2) to understand in situ regulation of cell type-specific gene expression and build integrated cell type-resolved models for tissue function and plasticity; and 3) to translate the integrated systems-level information from animal models to the clinical setting.