Single‐cell technologies that can quantify features of individual cells within a tumor are critical for treatment strategies aiming to target cancer cells while sparing or activating beneficial cells. Given that key players in protein networks are often the primary targets of precision oncology strategies, it is imperative to transcend the nucleic acid message and read cellular actions in human solid tumors. Here, we review the advantages of multiplex, single‐cell mass cytometry in tissue and solid tumor investigations. Mass cytometry can quantitatively probe nearly any cellular feature or target. In discussing the ability of mass cytometry to reveal and characterize a broad spectrum of cell types, identify rare cells, and study functional behavior through protein signaling networks in millions of individual cells from a tumor, this review surveys publications of scientific advances in solid tumor biology made with the aid of mass cytometry. Advances discussed include functional identification of rare tumor and tumor‐infiltrating immune cells and dissection of cellular mechanisms of immunotherapy in solid tumors and the periphery. The review concludes by highlighting ways to incorporate single‐cell mass cytometry in solid tumor precision oncology efforts and rapidly developing cytometry techniques for quantifying cell location and sequenced nucleic acids.