To learn content knowledge in science, technology, engineering, and math domains, students need to make connections among visual representations. This article considers two kinds of connection-making skills: (1) "sense-making skills" that allow students to verbally explain mappings among representations and (2) "perceptual fluency" in connection making that allows students to fast and effortlessly use perceptual features to make connections among representations. These different connection-making skills are acquired via different types of learning processes. Therefore, they require different types of instructional support: sense-making activities and fluency-building activities. Because separate lines of research have focused either on sense-making skills or on perceptual fluency, we know little about how these connection-making skills interact when students learn domain knowledge. This article describes two experiments that address this question in the context of undergraduate chemistry learning. In Experiment 1, 95 students were randomly assigned to four conditions that varied whether or not students received sense-making activities and fluency-building activities. In Experiment 2, 101 students were randomly assigned to five conditions that varied whether or not and in which sequence students received sense-making and fluency-building activities. Results show advantages for sense-making and fluency-building activities compared to the control condition only for students with high prior chemistry knowledge. These findings provide new insights into potential boundary conditions for the effectiveness of different types of instructional activities that support students in making connections among multiple visual representations.