Haematopoietic stem cell (HSC) transplantation (HSCT) is the only curative treatment for a broad range of haematological malignancies but the standard of care relies on untargeted chemotherapies and limited possibilities to treat malignant cells post HSCT without affecting the transplanted healthy cells. Antigen-specific cell depleting therapies hold the promise for much more targeted elimination of diseased cells, as witnessed in the past decade by the revolution of clinical practice for B cell-malignancies. However, target selection is complex and limited to antigens expressed on subsets of haematopoietic cells resulting in a fragmented therapy landscape with high development costs. Here, we demonstrate that an antibody-drug conjugate (ADC) targeting the pan-haematopoietic marker CD45 enabled antigen-specific depletion of the entire haematopoietic system including HSCs. Pairing this ADC with transplantation of human HSCs engineered to be shielded from the CD45-targeting ADC enabled selective eradication of leukaemic cells with preserved haematopoiesis. The CD45-ADC/engineered HSC pair creates a near-universal strategy to replace a diseased haematopoietic system, irrespective of disease aetiology or originating cell type. We propose that this approach could have broad implications beyond haematological malignancies.