The microenvironment acts as a conduit for cellular communication, delivering signals that direct development and sustain tissue homeostasis. In pathologies such as cancer, this integral function of the microenvironment is hijacked to support tumor growth and progression. Cells sense the microenvironment via signal transduction pathways culminating in altered gene expression. In addition to induced transcriptional changes, the microenvironment exerts its effect on the cell through regulation of post-transcriptional processes including alternative splicing and translational control. Here we describe how alternative splicing and protein translation are controlled by microenvironmental parameters such as oxygen availability. We also emphasize how these pathways can be utilized to support processes that are hallmarks of cancer such as angiogenesis, proliferation, and cell migration. We stress that cancer cells respond to their microenvironment through an integrated regulation of gene expression at multiple levels that collectively contribute to disease progression.