The use of unmanned aerial vehicles (UAVs), popularly known as drones, will be an integral component of emerging smart city applications ranging from delivery of goods to flying taxis. However, a seamless deployment of such drone-based applications requires addressing technical challenges across communications, security, autonomy, and control. In this talk, we focus on the wireless communications and security challenges of drone-based systems. From a communications perspective, UAVs can assume two roles: aerial base stations that enhance the coverage and capacity of wireless networks and flying users that require wireless cellular connectivity for enabling applications such as real-time streaming and item delivery. With this in mind, we introduce a foundational framework for designing three-dimensional (3D) wireless cellular networks that incorporate both drone base stations and cellular-connected drone users. For this novel 3D model, we study a number of key problems including drone deployment, network planning, and cell association. Then, we turn our attention to the cyber-physical security challenges brought forward by the deployment of drones. In this area, we present a holistic framework, with foundations in behavioral game theory, for addressing fundamental cyber-physical security problems pertaining to drone-based systems. In particular, we show how notions of risk, bounded rationality, and uncertainty can influence the security of drone-based systems and we develop new game-theoretic solutions that explicitly account for such factors in security analyses. We conclude by an overview on our ongoing research activities that cut across the areas of cyber-physical systems, wireless networks, game theory, machine learning, security, and control.