Neuromyelitis optica spectrum disorder (NMOSD) is a rare but debilitating autoimmune disease of the central nervous system (CNS) for which several biotherapies have recently been approved on the market. Historically, NMOSD disease-modifying treatments relied on wide-spectrum off-label immunosuppressants, such as azathioprine, mycophenolate mofetil, and cyclophosphamide. Since 2015, evidence has accumulated to support off-label biotherapies (rituximab and tocilizumab) and to approve satralizumab, inebilizumab, eculizumab, and ravulizumab. This next generation of drugs provides several targeted disease-modifying treatment options for NMOSD. Here, we review this modern panel. We first review the mechanistic rationales associated with their specific targets. We then review the pivotal evidence supporting their use in practice and their respective regimens. Lastly, we discuss the positioning of each therapeutic class. The current therapeutic options in NMOSD comprise three targeted mechanisms at different stages of a unique tissue-injury cascade: B-cell depleting, anti-cytokine, and anti-complement therapies. One drug has been approved on the market in each class. The current consensus proposes positioning the approved drugs as first-line treatments for newly-diagnosed patients and as alternative therapies in case of failure of historical treatment. Yet, there has been limited acceptance in practice due to high drug prices.