Over the past two decades, mitochondrial morphology, ultrastructure and interactions with other organelles have emerged as important regulators of cell physiology. Changes in mitochondrial shape, cristae architecture and interorganelle contacts control processes as diverse as apoptosis, inflammation, differentiation and tumorigenesis. However, how mitochondrial dynamics and organelle interactions integrate complex cellular cues to determine specific biological responses remains unclear. Here, we will revisit key experiments that established the functional links between mitochondrial shape, ultrastructure and interorganelle communication in physiology and disease. We will also discuss our efforts to define the mechanisms by which mitochondria communicate with other cellular compartments and the questions that remain unresolved. In particular, we will focus on the crosstalk between mitochondria and the endocytic pathway and on the mechanisms through which this communication may regulate complex cellular responses such as angiogenesis.