Most, if not all, aspects of carcinogenesis are influenced by the tumor microenvironment (TME), a complex architecture of cells, matrix components, soluble signals, and their dynamic interactions in the context of physical traits of the tissue. Expanding application of technologies for high-dimensional analyses with single-cell resolution has begun to decipher the contributions of the immune system to cancer progression and its implications for therapy. In this review, we will discuss the multifaceted roles of tumor-associated macrophages and neutrophils, focusing on factors that subvert tissue immune homeostasis and offer therapeutic opportunities for TME reprogramming. By performing a critical analysis of available datasets, we elaborate on diversification mechanisms and unifying principles of myeloid cell heterogeneity in human tumors. Article Note: This article is part of a series of reviews covering Genome Regulation in Innate and Adaptive Immune Cells appearing in Volume 300 of Immunological Reviews. Byline: Nicoletta Caronni, Elisa Montaldo, Luca Mezzanzanica, Francesco Cilenti, Marco Genua, Renato Ostuni