Modern approaches and technical developments in attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy are leading to new analytical science opportunities. As ATR-FTIR solidifies its foothold as a mature analytical tool, progressively implemented to clinical applications, microstructured internal reflection elements (μ-IREs) are becoming increasingly important. Fabricated into microgroove structures through anisotropic etching of commercially available silicon wafers, μ-IREs demonstrate both low cost and high performance and are thus gaining in popularity across a range of disciplines as alternatives to traditional IREs. This review summarizes recent progress and applications of μ-IREs and highlights their fabrication and use in quantitative spectroscopy and electrochemistry. The integration of μ-IREs in microfluidic devices and other analytical systems is discussed with consideration of device fabrication strategies, along with their suitability for both chemical spectroscopy and chemical imaging. Increased commercial availability of broadband IR laser sources and integration into microscale devices is predicted to drive continuing development of innovative uses of μ-IRE-based ATR-FTIR for a range of label-free diagnostic applications.