Digital tomosynthesis (DTS) is emerging as an advanced imaging technique that enables volumetric slice imaging with a detector typically used for projection radiography. An understanding of the interactions between DTS acquisition parameters and characteristics of the reconstructed slice images is required for optimizing the acquisition protocols of various clinical applications. This paper presents our investigation of the effects and interactions of acquisition parameters, including sweep angle, number of projections, and dose, on clinically relevant image-quality metrics. Metrics included the image characteristics of in-slice resolution, depth resolution, image noise level, and presence of ripple. Phantom experiments were performed to characterize the relationship between the acquisition parameters and image quality. Results showed that the depth resolution was mainly dependent on sweep angle. Visibility of ripple was determined by the projection density (number of projections divided by sweep angle), as well as properties of the imaged object. Image noise was primarily dependent on total dose and not significantly affected by the number of projections. These experimental and theoretical results were confirmed using anthropomorphic phantoms and also used to develop clinical acquisition protocols. Assessment of phantom and clinical images obtained with these protocols revealed that the use of acquisition protocols optimized for a given clinical exam enables rapid, low-dose, high quality DTS imaging for diverse clinical applications including abdomen, hand, shoulder, spine, and chest. We conclude that DTS acquisition parameters have a significant effect on image quality and should be tailored for the imaged anatomy and desired clinical application. Relationships developed in this work will guide the selection of acquisition protocols to improve image quality and clinical utility of DTS for a wide variety of clinical exams.