Integral membrane proteins are one of the most challenging groups of macromolecules despite their apparent conformational simplicity. They manage and drive transport, circulate information, and participate in cellular movements via interactions with other proteins and through intricate conformational changes. Their structural and functional decoding is challenging and has imposed demanding experimental development. Solution nuclear magnetic resonance (NMR) spectroscopy is one of the techniques providing the capacity to make a significant difference in the deciphering of the membrane protein structure-function paradigm. The method has evolved dramatically during the last decade resulting in a plethora of new experiments leading to a significant increase in the scientific repertoire for studying membrane proteins. Besides solving the three-dimensional structures using state-of-the-art approaches, a large variety of developments of well-established techniques are available providing insight into membrane protein flexibility, dynamics, and interactions. Inspired by the speed of development in the application of new strategies, by invention of methods to measure solvent accessibility and describe low-populated states, this review seeks to introduce the vast possibilities solution NMR can offer to the study of membrane protein structure-function analyses with special focus on applicability. © 2012 American Physiological Society. Compr Physiol 2:1491-1539, 2012.