Tumors and their infiltrating cells form a complex and heterogeneous (focal and cellular) microenvironment with paracrine and exocrine regulatory activities. The nature and mediators of the resulting molecular crosstalk are poorly defined and a better understanding is critical to controlling tumor progression and metastasis. Molecular and cellular signatures of tumors and peripheral blood can predict clinical outcomes; however, the origin and regulation of these signatures is obscure. To improve our understanding of this crosstalk, we examined tumor/infiltrating cell regulation of cellular and molecular targets in the regulation of the microenvironment, hematopoietic homeostasis, and molecular expression. These experiments used orthotopic metastatic (4T1) and non-metastatic (168-FARN) murine mammary tumors and revealed significant differences in the transcripts of metastatic and benign tumor cells (in vitro and in vivo) including growth factors (G-CSF, SCF), enzymes (NOS-2, MMP-13), interleukins (IL-23a), and chemokines (CXCL-5, CXCL-1, CCL-2). On a cellular level; differences between tumors in the frequency and number of splenic, blood and tumor-infiltrating T-, dendritic-, and myeloid-derived suppressor cells were observed. Unexpectedly, we also report differences in transcript levels between primary tumors and cultured tumor cells with significant increases in tumor expression of ARG-1 and VEGFa and decreased G-CSF, suggesting micro-environmental crosstalk regulation or contamination by infiltrating inflammatory cells. This was clarified using isolated infiltrating and splenic myeloid cells (>99% pure) demonstrating tumor induced changes to transcripts from infiltrating myeloid cells (VEGF-a, IL23a) and host regulation of tumor transcripts (ARG-1, G-CSF, CXCL5). Cellular studies revealed that metastatic tumors stimulated myelopoiesis and cellular trafficking independent of host cytokines, which based on NOS2 knockout mouse studies dampened rather than increased the inflammatory response. Together, these observations support a critical role for tumor microenvironmental-host crosstalk in the regulation of cellular and molecular phenotypes and tumor progression.