Recurrent spontaneous abortion (RSA), three or more pregnancy losses prior to 20 weeks, occurs in about 1% of all pregnancies, 50% of RSA cases remain unexplained and unresolved. Recently, immune pathways have been implicated in the pathophysiology of RSA. Immune tolerance of the fetal–placental unit and placental angiogenesis are mandatory for a successful pregnancy outcome. Unscheduled dysregulation of the placental vasculature is thought to be the pathophysiologic mechanisms underlying an array of pregnancy complications like infertility, miscarriage, pre-eclampsia, and fetal growth restriction and death. Investigations on mechanisms and management of RSA are mired by substandard design and lack of optimal randomized clinical trials and have resulted in disagreement on guidelines for evaluation and treatments for patients with multiple pregnancy losses of unknown etiology. The present review focuses on evidence-based research discussion with immunologic causes, and immune-regulatory therapies recommended for helping patients with a history of RSA. We highlight data that might support revalidation of low molecular weight heparin as a protective therapy in RSA. Newly launched growth factors, GM-CSF, and potentially novel agents to suppress inflammatory rejection, including regulatory T cells, human chorionic gonadotropin, and M-CSF/IL-10, may work in concert with tender-loving-care therapy and give hope to couples with multiple pregnancy losses.