Preclinical studies with mice have identified critical pathways that regulate CSC stemness and TAM biology (including recruitment, polarization, survival, and phagocytosis) during tumor progression. Targeting these key pathways can inhibit the properties of CSCs and TAMs and impair tumor progression. In addition to the pathways targeting either CSCs or TAMs, several pathways, including STAT3, PI3K, and CD47-SIRP1α, are involved in regulating the properties of both CSCs and TAMs, thus providing more-effective therapeutic strategies. Given the existence of CSC-TAM crosstalk during tumor progression, targeting CSC-TAM co-dependency is another promising cancer therapy strategy.