Machine learning plays an essential role in medical imaging. Pattern analysis techniques can identify, and quantify, subtle and spatially complex patterns of disease-induced changes in the brain despite confounding statistical noise and inter-individual variability. This allows the construction of sensitive biomarkers that can identify disease, or risk of developing it, and characterize future clinical progression on an individual patient basis. Thus pattern analysis techniques have become an indispensable part of the growing need for personalized, predictive medicine. However, despite important advances, several challenges remain before they can gain widespread acceptance as tools for precision diagnostics and prognostics in clinical practice. These include: (i) feature extraction and dimensionality reduction; (ii) readily interpreting complex multivariate models; and (iii) elucidating disease heterogeneity. In this chapter, we describe these challenges, putting emphasis on possible solutions, and present evidence of the usefulness of machine learning techniques at the clinical and research levels.