In 2013, California adopted the Next Generation Science Standards for California Public Schools, Kindergarten through Grade Twelve (CA NGSS), which set the stage for how science should be taught in every school throughout the state. Since the NGSS represent a change in how science instruction should be delivered, many teachers are now facing the difficult task of understanding these new ideas, identifying how their current instructional practices align with the NGSS, and translating and implementing these new practices in their classrooms. However, changing teacher instructional practices is not accomplished quickly or easily because teachers bring a variety of knowledge, beliefs, and experiences to standards-based reform efforts. As a result, when educational change is required, educators do not all respond the same way. Therefore, using a conceptual framework that drew upon literature on teacher sensemaking and policy interpretation in education, this mixed-method study investigated teachers’ experiences as they translated the NGSS into their own practice. This study centered on the perceptions and experiences of 37 secondary science teachers in two different high school districts in San Diego County. Based on survey and interview responses, findings from this study suggested that teachers were starting to develop some common language and understanding around the NGSS. Moreover, teachers had some understanding and knowledge of the instructional practices associated with the NGSS, which in turn was initiating changes in classroom practice. But teachers were less confident about their skills and knowledge regarding science and engineering practices and how to use the NGSS performance expectations to assess student learning. Additional findings also indicated that teacher beliefs, emotions, networks, and school contextual factors affected how teachers made sense of the NGSS.