The study of chemistry requires the understanding and use of spatial relationships, which can be challenging for many students. Prior research has shown that there is a need to develop students' spatial reasoning skills. To that end, this study implemented guided activities designed to strengthen students' spatial skills, with the aim of improving their understanding of spatial relationships that exist within and between molecules. Undergraduate STEM majors, taking the second semester of a two-semester general chemistry course, engaged in these activities. This study followed a quasi-experimental design, in which the experimental (n = 209) and the control group (n = 212) were administered a pre-test. At the completion of the semester, both groups participated in a post-test designed to measure spatial skill acquisition. A one-way ANOVA confirmed that student performance differed significantly between the three interventions and the control group. Students who completed three activities scored higher than those who completed only two, suggesting continuity is an important feature of spatial training. In particular, our results show improvement in three skill areas: symmetry plane identification, visualization of molecules and translation between 2D and 3D representations. The results of this study show that spatial skills can be successfully enhanced through the use of relevant guided activities designed to improve student understanding of external representations. Our findings show that the use of activities which require students to sketch molecular models from different perspectives, locate a plane of symmetry on a 3D model and on a 2D sketch of the same molecule, as well as position physical models to match 2D sketches containing dash/wedge cues is an effective approach to the teaching and learning of spatial skills in general chemistry.