Bone marrow (BM) is the primary site of adult blood production, hosting the majority of all hematopoietic stem and progenitor cells (HSPCs). Rare HSPCs are also found outside of the BM at steady state. In times of large hematopoietic demand or BM failure, substantial production of mature blood cells from HSPCs can occur in a number of tissues, in a process termed extramedullary hematopoiesis (EMH). Over the past decades, our understanding of BM hematopoiesis has advanced drastically. In contrast there has been very little focus on the study of extramedullary HSPC pools and their contributions to blood production. Here we summarize what is currently known about extramedullary HSPCs and EMH in mice and humans. We describe the evidence of existing extramedullary HSPC pools at steady state, then discuss their role in the hematopoietic stress response. We highlight that although EMH in humans is much less pronounced and likely physiologically distinct to that in mice, it can be informative about premalignant and malignant changes. Finally, we reflect on the open questions in the field and on whether a better understanding of EMH, particularly in humans, may have relevant clinical implications for hematological and nonhematological disorders.