In the age of high-throughput, single-cell biology, single-cell imaging has evolved not only in terms of technological advancements but also in its translational applications. The synchronous advancements of imaging and computational biology have produced opportunities of merging the two, providing the scientific community with tools towards observing, understanding, and predicting cellular and tissue phenotypes and behaviors. Furthermore, multiplexed single-cell imaging and machine learning algorithms now enable patient stratification and predictive diagnostics of clinical specimens. Here, we provide an overall summary of the advances in single-cell imaging, with a focus on high-throughput microscopy phenomics and multiplexed proteomic spatial imaging platforms. We also review various computational tools that have been developed in recent years for image processing and downstream applications used in biomedical sciences. Finally, we discuss how harnessing systems biology approaches and data integration across disciplines can further strengthen the exciting applications and future implementation of single-cell imaging on precision medicine. Keywords: high-throughput microscopy; machine learning; multiplex spatial imaging and multi-omics; precision medicine; single-cell imaging; systems biology.