Improved success of HLA-matched unrelated donor (MUD) hematopoietic stem cell transplantation (HCT) for severe aplastic anemia (SAA) over recent decades has impacted progressively on the indications and timing of this treatment modality. In the absence of a matched sibling donor (MSD), historically MUD HCT was reserved as an option after failure to respond to at least two courses of immunosuppressive therapy (IST) in adults with SAA, but with improved outcomes over time, it is now considered following response failure to one course of IST. Recent national and international studies and guidelines now recommend upfront MUD HCT as an option for children where a MUD is readily available, since outcomes are similar to MSD HCT. Fludarabine-based conditioning and the use of in vivo T-cell depletion with ATG or alemtuzumab have reported overall survival (OS) of > 85% in adult patients undergoing MUD HCT. However, in recent times, the use of eltrombopag in SAA has transformed the treatment landscape and there is currently much interest in its use with IST as upfront treatment, demonstrating high response rate in an early phase study. The risks of HCT, especially graft versus host disease (GVHD), need to be carefully balanced against the concerns of IST, namely relapse and later clonal evolution to myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML). In the absence of a current prospective randomized trial comparing these two approaches, in this review we examine the evidence for consideration of early MUD HCT in adults with SAA who would have been considered for MSD HCT but who lack a MSD, and where a MUD is readily available, and especially using an irradiation-free conditioning regimen, with a low risk of GVHD, as another treatment option. Such an option may be offered to patients to provide them with an informed choice, with the aim of cure of the disease rather than freedom from disease, relapse free survival or OS. Furthermore, understanding the immune signature for response to IST and the immunological responses to somatic mutations and clonal progression to MDS/AML may help define the future indication for upfront HCT and a precision medicine approach to therapy.