Single-cell technologies have revolutionized our ability to characterize biological systems. An exciting direction for quantitative biology is the recent emergence of spatial -omics technologies, which promise to spatially resolve single-cell measurements and allow us to study cell neighborhoods in unprecedented detail. In this talk, I will provide an overview of highly-multiplexed tissue imaging, a particular class of methods that uses fluorescence imaging to quantify dozens of protein targets at subcellular resolution. The talk will highlight important image analysis challenges conferred by these technologies and the steps we and others have taken to address them.