While advances in assisted reproductive techniques have been substantial, failure of the apparently viable embryo to implant remains a source of distress and frustration to patients and specialists alike. The unique maternal immunological response to the embryo and the notion that defects in early placentation underlie the great complications of pregnancy have focused attention on the therapeutic potential of peri-implantation immunomodulation. On the face of it, the rationale for this approach is very attractive. However, as will be argued in this review, the clinical evidence base supporting the use of immunosuppressive treatments is weak and difficult to apply in practice and fails the needs of both doctors and their patients. This evidence gap is filled by justifications that are based largely on meeting patient expectations and commercial imperatives. However, this does not mean that immunomodulation treatments should be written off as ineffective. The literature in this field, while suffering the same challenges of heterogeneity, small studies, and publication bias as other areas of medicine, does hint at the way forward. Recurrent implantation failure and pregnancy loss are not diagnoses but clinical presentations that require appropriate phenotyping and etiological investigation. We are increasingly gaining the tools to make an “endometrial diagnosis,” and these will allow us to design clinical studies of interventions that treat the underlying cause rather than the symptoms of implantation failure. The current evidence base does not support the clinical use of immunomodulation therapies in patients undergoing IVF. However, more discerning phenotyping may identify groups who could benefit.