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Due to its complexity, the study of normal and malignant hematopoiesis requires a multidisciplinary approach. The use of mathematical models for understanding cell population dynamics, the development of cancers, or the effect of a treatment is particularly appropriate. Mathematical models, calibrated from experimental observations, can be used as clinical decision-making tools, allowing, for example, us to predict a treatment’s effect or optimize its dosage. In this review, we will start by presenting different mathematical models and formalisms that have been developed over the decades to model hematopoiesis, some of which are still the basis of the most recent work. We will then discuss methodological issues related to mathematical inference to ensure the validity and robustness of the results. Finally, we will illustrate the use of mathematical models in three fields of application: the initiation and development of hematological malignancies, the deregulation of their hematopoiesis, and their treatment.