This chapter introduces some basic questions and concepts related to the semiotic study of culture and of cultures. The first question "Is semiotics necessary to life?" leads to the analysis of the role of semiotics and semioticness vis-à-vis human beings. The chapter suggests a double necessity of semiotics, intended both as a quality proper to humankind and as a scientific knowledge necessary to reflect and develop awareness of our unperceived "cultural nature." The second question is related to a basic and yet forgotten claim of semiotics. This is the idea that regards semiotic analysis not only as a form of intellectual knowledge but also as an action that aims to transform reality. This leads to the definition of the semiotician as a political subject, and to the reflection about the general status of subject and subjectivity from a semiotic point of view. The third question confronts the paradox of a cultural space that is always singular and plural at the same time. The chapter proposes some theoretical and methodological tools—e.g., the circular intellectual movement represented by analysis and catalysis—in order to manage the complex relations between parts and whole, micro and macro, order and chaos, and sense and nonsense. The second part of the chapter proposes three key concepts for the contemporary and for a future semiotics of culture(s): semiosphere, formation, and translation. Starting from the structural paradoxes of the idea of semiosphere, developed in the 1980s by Juri Lotman, the chapter proposes a dynamic and glocal idea of culture(s) based on a relationalist approach. The idea of formation enables the mapping of different types of semiotic relations pertaining to the study of culture. At the same time, the concept of formation encapsulates the concepts of sign, text, discourse, and language. The concept of formation assumes a central role in the description of the various modes of translation and in the understanding of the implications of translation on the constitution or on the transformation of common sense and reality. The chapter proposes to consider translation as a key concept that allows the articulation of different semiotic visions and schools as well as the analysis of some of the most interesting and thorny dynamics and devices of actual cultural life.