<p>Hybrid engineered biological systems integrate electronics and microfluidics with engineered biological components, such as microbes or cell-free DNA-based systems, to effectively sense, act upon and report on biological environments. As these engineered biological systems become essential in addressing challenges in healthcare, environmental monitoring, remediation and agriculture, this Review offers an in-depth discussion of their applications, critical design choices and challenges. Alongside an overview of the state of the field, we present a classification framework aimed at helping researchers make informed and optimized design decisions tailored to the intended biological application. Furthermore, we outline how the development of cyber-secure biological systems could enhance the security and functionality of engineered biological platforms. Last, we introduce a ‘Living Roadmap’ (<a href="https://www.programmingbiology.org/csbs">https://www.programmingbiology.org/csbs</a>) to dynamically reflect the field’s progress and support continuous monitoring of future advancements.</p>