Status epilepticus (SE) is one of the most frequent neurologic emergencies, and a rapid and effective treatment is warranted. Current guidelines recommend a stepwise approach using a sequence of different antiepileptic drugs with benzodiazepines (BZD) being the first treatment proposed. To provide the more effective treatment as soon as possible, some authors have suggested using a combined polytherapy as first-line treatment. Strong evidence supports the use of benzodiazepines, mostly lorazepam and midazolam as initial monotherapy treatment for SE. Insufficient data are available to support the use of nonsedating antiepileptic drugs as phenytoin, valproic acid, or levetiracetam without a previous benzodiazepine administration. Studies assessing the role of a combined initial therapy are rare, if not missing. Moreover, owing the wide range of SE etiologies, a "one fits all" initial polytherapy seems difficult to achieve. After reviewing the available evidence, guidelines, and current practices regarding monotherapy and polytherapy as first-line treatment in SE in adults, the authors propose a rational algorithm for early antiseizure treatment in SE.