Alpha-radiotherapy is an internal radiation therapy based on the use of α-particle emitters. These radionuclides are highly cytotoxic and altogether their characteristics make them of particular interest in the treatment of disseminated cancers, minimal residual disease, and micro-metastases. Nowadays there is a growing interest for these α-emitters whose development in the clinic was so far limited. Indeed remarkable clinical results have been observed in hematological malignancies and lately in metastatic castration-resistant prostate cancer. Apart from their direct cytotoxic potential on tumor cells, studies have also investigated the bystander effects of alpha-radiotherapy, in particular on the tumor microenvironment including the vascular and the immune components. Depending on the type of tumor and on the α-radionuclide, the scope of these studies could help specify the optimal conditions for the use of alpha-radiotherapy as well as the combination therapies most likely to potentiate tumor eradication. In this chapter we review and discuss the preclinical in vitro and in vivo studies that have analyzed the impact of α-particle emitters on the tumor microenvironment as well as the few combination therapies that have been reported so far.