In modern-data analysis applications, the abundance of data makes extracting meaningful information from it challenging, in terms of computation, storage, and interpretability. In this setting, exploiting sparsity in data has been essential to the development of scalable methods to problems in machine learning, statistics and signal processing. However, in various applications, the input variables exhibit structure beyond simple sparsity. This motivated the introduction of structured sparsity models, which capture such sophisticated structures, leading to a significant performance gains and better interpretability. Structured sparse approaches have been successfully applied in a variety of domains including computer vision, text processing, medical imaging, and bioinformatics. The goal of this thesis is to improve on these methods and expand their success to a wider range of applications. We thus develop novel methods to incorporate general structure a priori in learning problems, which balance computational and statistical efficiency trade-offs. To achieve this, our results bring together tools from the rich areas of discrete and convex optimization. Applying structured sparsity approaches in general is challenging because structures encountered in practice are naturally combinatorial. An effective approach to circumvent this computational challenge is to employ continuous convex relaxations. We thus start by introducing a new class of structured sparsity models, able to capture a large range of structures, which admit tight convex relaxations amenable to efficient optimization. We then present an in-depth study of the geometric and statistical properties of convex relaxations of general combinatorial structures. In particular, we characterize which structure is lost by imposing convexity and which is preserved. We then focus on the optimization of the convex composite problems that result from the convex relaxations of structured sparsity models. We develop efficient algorithmic tools to solve these problems in a non-Euclidean setting, leading to faster convergence in some cases. Finally, to handle structures that do not admit meaningful convex relaxations, we propose to use, as a heuristic, a non-convex proximal gradient method, efficient for several classes of structured sparsity models. We further extend this method to address a probabilistic structured sparsity model, we introduce to model approximately sparse signals.