Continuing development of the technology and applications of field asymmetric waveform ion mobility spectrometry (FAIMS) calls for better understanding of its limitations and factors that govern them. While key performance metrics such as resolution and ion transmission have been calculated for specific cases employing numerical simulations, the underlying physical trends remained obscure. Here we determine that the resolving power of planar FAIMS scales as the square root of separation time and sensitivity drops exponentially at the rate controlled by absolute ion mobility and several instrument parameters. A strong dependence of ion transmission on mobility severely discriminates against species with higher mobility, presenting particular problems for analyses of complex mixtures. While the time evolution of resolution and sensitivity is virtually identical in existing FAIMS systems using gas flow and proposed devices driven by electric field, the distributions of separation times are not. The inverse correlation between mobility (and thus diffusion speed) and residence time for ions in field-driven FAIMS greatly reduces the mobility-based discrimination and provides much more uniform separations. Under typical operating conditions, the spread of elimination rates for commonly analyzed ions is reduced from Ͼ5 times in flow-driven to 1.6 times in field-driven FAIMS while the difference in resolving power decreases from ϳ60% to ϳ15%. ield asymmetric waveform ion mobility spectrometry (FAIMS) has emerged as a powerful new analytical technique [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. All IMS methods separate ions using their transport in a gas under the influence of electric field [21]: conventional IMS is based on absolute ion mobility (K) at particular field intensity (E) and FAIMS works with the difference between K at high and low E. So FAIMS is also known as differential mobility spectrometry (DMS) [11,12]. The value of K for all ions increases or decreases at sufficiently high E, depending on the interaction potentials with gas molecules. As those potentials differ for different ions, the K(E) function is characteristic of the species and, in principle, any two could be distinguished by FAIMS.Separation parameters in FAIMS are largely independent of the ion mass/charge state (m/z) ratio, which renders FAIMS substantially orthogonal to mass spectrometry (MS) and makes FAIMS/MS a powerful method of broad utility. The separation power of FAIMS/MS could be augmented by coupling to conventional IMS providing 2-D separations [17,18] before MS and/or pre-ionization stages such as liquid or gas chromatography (LC [14,16,20] or GC [5,8,9]) or capillary electrophoresis (CE) [10]. The operational simplicity, small size, and low cost make FAIMS attractive for field analyses that require rugged, portable, inexpensive sensors. Recent commercialization of FAIMS technology, alone and in conjunction with LC/MS or GC, has enabled its expansion into proteomics [15][16][17], structural biology [...