Three-day artemisinin-based combination therapy (ACT) is the current standard of care for the treatment of malaria. However, specific drug resistance associated with reduced efficacy of ACT has been observed, therefore necessitating the clinical development of new anti-malarial drugs and drug combinations. Previously, Single Encounter Radical Cure and Prophylaxis (SERCAP) has been proposed as ideal target-product-profile for any new anti-malarial drug regimen as this would improve treatment adherence besides ensuring complete cure and prevention of early reinfection. Arguably, this concept may not be ideal as it (1) necessitates administration of an excessively high dose of drug to achieve plasmodicidal plasma levels for a sufficient time span, (2) increases the risk for drug related adverse drug reactions, and (3) leaves the patient with a one-time opportunity to achieve—or not—cure by a single drug intake. Over the past years, SERCAP has led to the halt of promising drug development programmes, leading to potentially unnecessary attrition in the anti-malarial development pipeline. One proposition could be the concept of single-day multi-dose regimens as a potentially better alternative, as this allows to (1) administer a lower dose of the drug at each time-point leading to better tolerability and safety, (2) increase treatment adherence based on the intake of the anti-malarial drug within 24 h when malaria-related symptoms are still present, and (3) have more than one opportunity for adequate intake of the drug in case of early vomiting or other factors causing reduced bioavailability. In line with a recently published critical viewpoint on the concept of SERCAP, an alternative proposition is—in contrast to the current World Health Organization (WHO) treatment guidelines—to aim for less than three days, but still multiple-dose anti-malarial treatment regimens. This may help to strike the optimal balance between improving treatment adherence, maximizing treatment effectiveness, while keeping attrition of new drugs and drug regimens as low as possible.