Precise replacement of diseased or dysfunctional organs is the goal of regenerative medicine and has appeared to be a distant goal for a long time. In the field of hematopoietic stem cell transplantation, this goal is now becoming tangible as gene-editing technologies and novel conditioning agents are entering the clinical arena. Targeted immunological depletion of hematopoietic stem cells (HSC), which are at the very root of the hematopoietic system, will enable a more selective and potentially more effective hematopoietic stem cell transplantation of patients with hematological diseases. In contrast to current conditioning regimes which are based on ionizing radiation and chemotherapy, immunological conditioning will spare mature hematopoietic cells and cause substantially less inflammation and unspecific collateral damage to other organs. Biological agents which target the stem cell antigen CD117 are the front-runners for this purpose and show preclinical activity in depletion of healthy HSC. The value of anti-CD117 antibodies as conditioning agents is currently evaluated in early clinical trials. Whereas mild, antibody-based immunological conditioning concepts might be appropriate for benign hematological conditions in which incomplete replacement of diseased cells is sufficient, higher efficacy will be required for treatment and elimination of hematologic stem cell malignancies such as Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS). Antibody-drug conjugates, bispecific T-cell engaging and activating antibodies (TEA) or CAR T-cells might offer increased efficacy compared to naked antibodies and yet higher tolerability and safety compared to current genotoxic conditioning approaches. Here, we summarize the current state regarding immunological conditioning concepts for the treatment of HSC disorders and outline potential future developments.