Abstract: For decades, the search for potential signs of Martian life has attracted strong international interest and has led to significant planning and scientific implementation. Clearly, in order to detect potential life signals beyond Earth, fundamental questions, such as how to define such terms as “life” and “biosignature”, have been given considerable attention. Due to the high costs of direct exploration of Mars, Mars-like regions on Earth have been invaluable targets for astrobiological research, places where scientists could practice the search for “biosignatures” and refine ways to detect them. This review summarizes scientific instrumental techniques that have resulted from this work. Instruments must necessarily be our “eyes” and “hands” as we attempt to identify and quantify biosignatures on Mars. Scientific devices that can be applied in astrobiology include mass spectrometers and electromagnetic-spectrum-based spectrometers, redox potential indicators, circular dichroism polarimeters, in situ nucleic acid sequencers, life isolation/cultivation systems, and imagers. These devices and how to interpret the data they collect have been tested in Mars-analog extreme environments on Earth to validate their practicality on Mars. To anticipate the challenges of instrumental detection of biosignatures through the full evolutionary history of Mars, Terrestrial Mars analogs are divided into four major categories according to their similarities to different Martian geological periods (the Early−Middle Noachian Period, the Late Noachian−Early Hesperian Period, the Late Hesperian−Early Amazonian Period, and the Middle−Late Amazonian Period). Future missions are suggested that would focus more intensively on Mars’ Southern Hemisphere, once landing issues there are solved by advances in spacecraft engineering, since exploration of these early terrains will permit investigations covering a wider continuum of the shifting habitability of Mars through its geological history. Finally, this paper reviews practical applications of the range of scientific instruments listed above, based on the four categories of Mars analogs here on Earth. We review the selection of instruments suitable for autonomous robotic rover tests in these Mars analogs. From considerations of engineering efficiency, a Mars rover ought to be equipped with as few instrument assemblies as possible. Therefore, once candidate landing regions on Mars are defined, portable suites of instruments should be smartly devised on the basis of the known geological, geochemical, geomorphological, and chronological characteristics of each Martian landing region. Of course, if Mars sample-return missions are successful, such samples will allow experiments in laboratories on Earth that can be far more comprehensive and affordable than is likely to be practicable on Mars. To exclude false positive and false negative conclusions in the search for extraterrestrial life, multiple diverse and complementary analytical techniques must be combined, replicated, and carefully interpreted. The question of whether signatures of life can be detected on Mars is of the greatest importance. Answering that question is extremely challenging but appears to have become manageable.