Microsystems are increasingly being applied in harsh and/or inaccessible environments, but many markets expect the same level of functionality for long periods of time. Harsh environments cover areas that can be subjected to high temperature, (bio)-chemical and mechanical disturbances, electromagnetic noise, radiation, or high vacuum. In the field of actuators, the devices must maintain stringent accuracy specifications for displacement, force, and response times, among others. These new requirements present additional challenges in the compensation for or elimination of cross-sensitivities. Many state-of-the-art precision devices lose their precision and reliability when exposed to harsh environments. It is also important that advanced sensor and actuator systems maintain maximum autonomy such that the devices can operate independently with low maintenance. The next-generation microsystems will be deployed in remote and/or inaccessible and harsh environments that present many challenges to sensor design, materials, device functionality, and packaging. All of these aspects of integrated sensors and actuator microsystems require a multidisciplinary approach to overcome these challenges. The main areas of importance are in the fields of materials science, micro/nano-fabrication technology, device design, circuitry and systems, (first-level) packaging, and measurement strategy. This study examines the challenges presented by harsh environments and investigates the required approaches. Examples of successful devices are also given.