Vaccines are urgently needed to reduce the burden of malaria and enable progress towards malaria elimination. However, the most advanced malaria vaccines have only achieved low to moderate protective efficacy in clinical trials in endemic populations. The sporozoite form of malaria is inoculated into the skin during an infected mosquito bite and targeting sporozoites by vaccines is an attractive strategy to prevent infection and subsequent clinical illness. We have established that following inoculation, sporozoites can be opsonized by antibodies and cleared by peripheral blood leukocytes, especially neutrophils, with additional roles for monocytes and natural killer cells. We identified the activating low affinity Fcγ receptors (FcγR), including FcγRIIa and FcγRIIIa/b, as critical for this activity. We established that the circumsporozoite protein (CSP) is the major target of antibodies that promote opsonic phagocytosis and defined the activity of antibodies to different regions of CSP. We identified epitopes within the N-terminal region of CSP that are targeted by functional antibodies, and these epitopes are not included in current malaria vaccines. Immunization with full-length CSP was inefficient at inducing antibodies to the N-terminal region and investigation among adults in malaria-endemic regions revealed the N-terminal domain of CSP is also a less prominent target of antibodies acquired through natural exposure. Subsequently, we have developed multiple strategies to improve the immunogenicity of this region and maximize the induction of functional antibodies that mediate protective immunity. Our data highlight the importance of FcγR-mediated opsonic phagocytosis in immunity against sporozoites, and specific epitopes of CSP, and reveal potential new strategies for developing a highly effective vaccine using epitope targeting approaches and peptide-based immunogens.