The Internet of Things (IoT) technology is transforming the world into Smart Cities, which have a huge impact on future societal lifestyle, economy and business. Intelligent Transportation Systems (ITS), especially IoT-enabled Electric Vehicles (EVs), are anticipated to be an integral part of future Smart Cities. Assuring ITS safety and security is critical to the success of Smart Cities because human lives are at stake. The state-of-the-art understanding of this matter is very superficial because there are many new problems that have yet to be investigated. For example, the cyber-physical nature of ITS requires considering human-in-the-loop (i.e., drivers and pedestrians) and imposes many new challenges. In this paper, we systematically explore the threat model against ITS safety and security (e.g., malfunctions of connected EVs/transportation infrastructures, driver misbehavior and unexpected medical conditions, and cyber attacks). Then, we present a novel and systematic ITS safety and security architecture, which aims to reduce accidents caused or amplified by a range of threats. The architecture has appealing features: (i) it is centered at proactive cyber-physical-human defense; (ii) it facilitates the detection of early-warning signals of accidents; (iii) it automates effective defense against a range of threats.