Based on the Venturi self-pumping effect, real-time sniffing with mass spectrometry (R-sniffing MS) is developed as a tool for direct and real-time mass spectrometric analysis of both gaseous and solid samples. It is capable of dual-mode operation in either gaseous or solid phase, with the corresponding techniques termed as Rg-sniffing MS and Rs-sniffing MS, respectively. In its gaseous mode, Rg-sniffing MS is capable of analyzing a gaseous mixture with response time (0.8–2.1 s rise time and 7.3–9.6 s fall time), spatial resolution (<80 μm), three-dimensional diffusion imaging, and aroma distribution imaging of red pepper. In its solid mode, an appropriate solvent droplet desorbs the sample from a solid surface, followed by the aspiration of the mixture using the Venturi self-pumping effect into the mass spectrometer, wherein it is ionized by a standard ion source. Compared with the desorption electrospray ionization (DESI) technique, Rs-sniffing MS demonstrated considerably improved limit of detection (LOD) values for arginine (0.07 μg/cm2 Rs-sniffing vs 1.47 μg/cm2 DESI), thymopentin (0.10 μg/cm2 vs 2.67 μg/cm2), and bacitracin (0.16 μg/cm2 vs 2.28 μg/cm2). Rs-sniffing is applicable for the detection of C60(OCH3)6Cl–, an intermediate in the methoxylation reaction involving C60Cl6 (solid) and methanol (liquid). The convenient and highly sensitive R-sniffing MS has a characteristic separation of desorption from the ionization process, in which the matrix atmosphere of desorption can be interfaced by a pipe channel and self-pumped by the Venturi effect with consequent integration using a standard ion source. The R-sniffing MS operates in a voltage-, heat-, and vibration-free environment, wherein the analyte is ionized by a standard ion source. Consequently, a wide range of samples can be analyzed simultaneously by the R-sniffing MS technique, regardless of their physical state.