Current ion mobility spectrometry (IMS) devices are used to detect drugs and explosives in the form of particles and, in cases where the vapor pressure of the drugs or explosives is sufficiently high, the gas can be sampled and detected directly. The aim of this study is to demonstrate the use of solid phase microextraction (SPME) as a preconcentration technique coupled to an IMS for the detection of odor signature compounds of drugs and explosives. The reduced mobilities (K(o)) and IMS operating conditions for the odor signature compounds of cocaine, marijuana, and 3,4-methylenedioxy-N-methylamphetamine (MDMA) are reported for the first time. LODs, linear dynamic ranges (LDRs), and the precision of the analysis of these odor signature compounds, and the explosive taggant 2,3-dimethyl-2,3-dinitrobutane (DMNB) were obtained by SPME-IMS and normal IMS conditions. The systematic optimization of the IMS operating parameters for the detection of these odor compounds is also reported incorporating the use of genetic algorithms (GAs) for finding the optimal settings for the detection of these compounds of interest. These results support the case for targeting volatile components as a presumptive detection for the presence of the parent compounds of drugs and explosives. Furthermore, the IMS-specific GA developed can be used as an optimization tool for the detection of other compounds of interest in future work.