Most fatalities from cancer are caused by metastases produced by circulating tumor cells (CTCs). Despite its importance, CTC diagnosis at an early treatable stage of disease is challenging. Early CTCs can escape from routine blood tests because they are rare events and can migrate between lymph and blood systems. To solve this problem, we introduced photoacoustic flow cytometry in vivo. This clinically-relevant technology is capable of noninvasively counting blood and lymphatic CTCs over disease progression with >1000-times higher sensitivity than existing methods. Here we summarize our preclinical results demonstrating advances of combined lymph+blood diagnosis of CTCs using metastatic melanoma model.