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The ever-increasing malware variants pose serious challenges for traditional signature-based anti-virus (AV) scan engines. To effectively handle the scale and magnitude of new malware variants, AV functionality is being moved from the user desktop into the cloud. AV in-the-cloud service is becoming the next-generation security infrastructure designed to defend against virus threats. It provides reliable protection service delivered through data centers worldwide, which are built on virtualization technologies. Nowadays, cloud-based security services are gaining bullish projections in both consumer and enterprise markets. However, are we getting ready for the cloud evolution? Security vendors are facing various challenges regarding the architectural design, implementation, and validation. Owing to the lack of operation standards among vendors and very few research works conducted up to this point, researchers have no references of AV cloud testing to rely on. In this paper, the architecture of AV in-the-cloud service is described. The challenges and solutions are discussed and illustrated by examples taken from our cutting-edge research on practical applications. Copyright © 2012 John Wiley & Sons, Ltd.